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BBA - Proteins and Proteomics (v.1824, #1)
Special issue: Proteolysis 50 years after the discovery of lysosome in honor of Christian de Duve
by Vito Turk (pp. 1-2).
Special issue: Proteolysis 50 years after the discovery of lysosome in honor of Christian de Duve
by Vito Turk (pp. 1-2).
Special issue: Proteolysis 50 years after the discovery of lysosome in honor of Christian de Duve
by Vito Turk (pp. 1-2).
Intracellular protein degradation: From a vague idea thru the lysosome and the ubiquitin–proteasome system and onto human diseases and drug targeting by Aaron Ciechanover (pp. 3-13).
Between the 1950s and 1980s, scientists were focusing mostly on how the genetic code was transcribed to RNA and translated to proteins, but how proteins were degraded had remained a neglected research area. With the discovery of the lysosome by Christian de Duve it was assumed that cellular proteins are degraded within this organelle. Yet, several independent lines of experimental evidence strongly suggested that intracellular proteolysis was largely non-lysosomal, but the mechanisms involved have remained obscure. The discovery of the ubiquitin–proteasome system resolved the enigma. We now recognize that degradation of intracellular proteins is involved in regulation of a broad array of cellular processes, such as cell cycle and division, regulation of transcription factors, and assurance of the cellular quality control. Not surprisingly, aberrations in the system have been implicated in the pathogenesis of human disease, such as malignancies and neurodegenerative disorders, which led subsequently to an increasing effort to develop mechanism-based drugs. This article is part of a Special Issue entitled: Proteolysis 50 years after the discovery of lysosome.► Discovery (along with Profs. Hershko and Rose) of the ubiquitin proteolytic system. ► Ubiquitin-mediated degradation of transcription factors. ► Regulation of the ubiquitin system components by ubiquitination and degradation. ► Recognition and targeting signals for ubiquitination and proteasomal degradation. ► History of the research area of intracellular proteolysis.
Keywords: Abbreviations; ODC; ornithine decarboxylase; G6PD; glucose-6-phosphate dehydrogenase; PEPCK; phosphoenol-pyruvate carboxykinase; TAT; tyrosine aminotransferase; APF-1; ATP-dependent proteolysis factor 1 (ubiquitin); UBIP; ubiquitous immunopoietic polypeptide (ubiquitin); MCP; multicatalytic proteinase complex (26S proteasome); CP; 20S core particle (of the proteasome); RP; 19S regulatory particle (of the proteasome)Proteolysis; Lysosome; Ubiquitin; Proteasome; Diseases
Intracellular protein degradation: From a vague idea thru the lysosome and the ubiquitin–proteasome system and onto human diseases and drug targeting by Aaron Ciechanover (pp. 3-13).
Between the 1950s and 1980s, scientists were focusing mostly on how the genetic code was transcribed to RNA and translated to proteins, but how proteins were degraded had remained a neglected research area. With the discovery of the lysosome by Christian de Duve it was assumed that cellular proteins are degraded within this organelle. Yet, several independent lines of experimental evidence strongly suggested that intracellular proteolysis was largely non-lysosomal, but the mechanisms involved have remained obscure. The discovery of the ubiquitin–proteasome system resolved the enigma. We now recognize that degradation of intracellular proteins is involved in regulation of a broad array of cellular processes, such as cell cycle and division, regulation of transcription factors, and assurance of the cellular quality control. Not surprisingly, aberrations in the system have been implicated in the pathogenesis of human disease, such as malignancies and neurodegenerative disorders, which led subsequently to an increasing effort to develop mechanism-based drugs. This article is part of a Special Issue entitled: Proteolysis 50 years after the discovery of lysosome.► Discovery (along with Profs. Hershko and Rose) of the ubiquitin proteolytic system. ► Ubiquitin-mediated degradation of transcription factors. ► Regulation of the ubiquitin system components by ubiquitination and degradation. ► Recognition and targeting signals for ubiquitination and proteasomal degradation. ► History of the research area of intracellular proteolysis.
Keywords: Abbreviations; ODC; ornithine decarboxylase; G6PD; glucose-6-phosphate dehydrogenase; PEPCK; phosphoenol-pyruvate carboxykinase; TAT; tyrosine aminotransferase; APF-1; ATP-dependent proteolysis factor 1 (ubiquitin); UBIP; ubiquitous immunopoietic polypeptide (ubiquitin); MCP; multicatalytic proteinase complex (26S proteasome); CP; 20S core particle (of the proteasome); RP; 19S regulatory particle (of the proteasome)Proteolysis; Lysosome; Ubiquitin; Proteasome; Diseases
Intracellular protein degradation: From a vague idea thru the lysosome and the ubiquitin–proteasome system and onto human diseases and drug targeting by Aaron Ciechanover (pp. 3-13).
Between the 1950s and 1980s, scientists were focusing mostly on how the genetic code was transcribed to RNA and translated to proteins, but how proteins were degraded had remained a neglected research area. With the discovery of the lysosome by Christian de Duve it was assumed that cellular proteins are degraded within this organelle. Yet, several independent lines of experimental evidence strongly suggested that intracellular proteolysis was largely non-lysosomal, but the mechanisms involved have remained obscure. The discovery of the ubiquitin–proteasome system resolved the enigma. We now recognize that degradation of intracellular proteins is involved in regulation of a broad array of cellular processes, such as cell cycle and division, regulation of transcription factors, and assurance of the cellular quality control. Not surprisingly, aberrations in the system have been implicated in the pathogenesis of human disease, such as malignancies and neurodegenerative disorders, which led subsequently to an increasing effort to develop mechanism-based drugs. This article is part of a Special Issue entitled: Proteolysis 50 years after the discovery of lysosome.► Discovery (along with Profs. Hershko and Rose) of the ubiquitin proteolytic system. ► Ubiquitin-mediated degradation of transcription factors. ► Regulation of the ubiquitin system components by ubiquitination and degradation. ► Recognition and targeting signals for ubiquitination and proteasomal degradation. ► History of the research area of intracellular proteolysis.
Keywords: Abbreviations; ODC; ornithine decarboxylase; G6PD; glucose-6-phosphate dehydrogenase; PEPCK; phosphoenol-pyruvate carboxykinase; TAT; tyrosine aminotransferase; APF-1; ATP-dependent proteolysis factor 1 (ubiquitin); UBIP; ubiquitous immunopoietic polypeptide (ubiquitin); MCP; multicatalytic proteinase complex (26S proteasome); CP; 20S core particle (of the proteasome); RP; 19S regulatory particle (of the proteasome)Proteolysis; Lysosome; Ubiquitin; Proteasome; Diseases
The endosome–lysosome pathway and information generation in the immune system by Colin Watts (pp. 14-21).
For a long time the lysosomal pathway was thought to be exclusively one for catabolism and recycling of material taken up by endocytosis from the external milieu or from the cytosol by autophagy. At least in the immune system it is clear now that endo/lysosomal proteolysis generates crucially important information, in particular peptides that bind class II MHC molecules to create ligands for survey by the diverse antigen receptors of the T lymphocyte system. This process of antigen processing and presentation is used to display not only foreign but also self peptides and therefore is important for ‘self’ tolerance as well as immunity to pathogens. Some cells, macrophages and particularly dendritic cells can load peptides on class I MHC molecules in the endosome system through the important, though still not fully characterised, pathway of cross-presentation. Here I try to provide a brief review of how this area developed focussing to some extent our own contributions to understanding the class II MHC pathway. I also mention briefly recent work of others showing that proteolysis along this pathway turns out to regulate immune signalling events in the innate immune system such as the activation of some members of the Toll-like receptor family. Finally, our recent work on the endo/lysosome targeted protease inhibitor cystatin F, suggests that auto-regulation of protease activity in some immune cells occurs. This article is part of a Special Issue entitled: Proteolysis 50years after the discovery of lysosome.► The original view of lysosomes as exclusively destructive organelles has changed. ► Controlled proteolysis in endo-lysosomes is needed for immunity. ► Antigen presentation and sensing of some microbial products requires protease action. ► Cystatin F may attenuate potentially toxic protease levels in some immune cells.
Keywords: Keyword; Endosome–lysosome pathway
The endosome–lysosome pathway and information generation in the immune system by Colin Watts (pp. 14-21).
For a long time the lysosomal pathway was thought to be exclusively one for catabolism and recycling of material taken up by endocytosis from the external milieu or from the cytosol by autophagy. At least in the immune system it is clear now that endo/lysosomal proteolysis generates crucially important information, in particular peptides that bind class II MHC molecules to create ligands for survey by the diverse antigen receptors of the T lymphocyte system. This process of antigen processing and presentation is used to display not only foreign but also self peptides and therefore is important for ‘self’ tolerance as well as immunity to pathogens. Some cells, macrophages and particularly dendritic cells can load peptides on class I MHC molecules in the endosome system through the important, though still not fully characterised, pathway of cross-presentation. Here I try to provide a brief review of how this area developed focussing to some extent our own contributions to understanding the class II MHC pathway. I also mention briefly recent work of others showing that proteolysis along this pathway turns out to regulate immune signalling events in the innate immune system such as the activation of some members of the Toll-like receptor family. Finally, our recent work on the endo/lysosome targeted protease inhibitor cystatin F, suggests that auto-regulation of protease activity in some immune cells occurs. This article is part of a Special Issue entitled: Proteolysis 50years after the discovery of lysosome.► The original view of lysosomes as exclusively destructive organelles has changed. ► Controlled proteolysis in endo-lysosomes is needed for immunity. ► Antigen presentation and sensing of some microbial products requires protease action. ► Cystatin F may attenuate potentially toxic protease levels in some immune cells.
Keywords: Keyword; Endosome–lysosome pathway
The endosome–lysosome pathway and information generation in the immune system by Colin Watts (pp. 14-21).
For a long time the lysosomal pathway was thought to be exclusively one for catabolism and recycling of material taken up by endocytosis from the external milieu or from the cytosol by autophagy. At least in the immune system it is clear now that endo/lysosomal proteolysis generates crucially important information, in particular peptides that bind class II MHC molecules to create ligands for survey by the diverse antigen receptors of the T lymphocyte system. This process of antigen processing and presentation is used to display not only foreign but also self peptides and therefore is important for ‘self’ tolerance as well as immunity to pathogens. Some cells, macrophages and particularly dendritic cells can load peptides on class I MHC molecules in the endosome system through the important, though still not fully characterised, pathway of cross-presentation. Here I try to provide a brief review of how this area developed focussing to some extent our own contributions to understanding the class II MHC pathway. I also mention briefly recent work of others showing that proteolysis along this pathway turns out to regulate immune signalling events in the innate immune system such as the activation of some members of the Toll-like receptor family. Finally, our recent work on the endo/lysosome targeted protease inhibitor cystatin F, suggests that auto-regulation of protease activity in some immune cells occurs. This article is part of a Special Issue entitled: Proteolysis 50years after the discovery of lysosome.► The original view of lysosomes as exclusively destructive organelles has changed. ► Controlled proteolysis in endo-lysosomes is needed for immunity. ► Antigen presentation and sensing of some microbial products requires protease action. ► Cystatin F may attenuate potentially toxic protease levels in some immune cells.
Keywords: Keyword; Endosome–lysosome pathway
Lysosomes and lysosomal cathepsins in cell death by Urška Repnik; Veronika Stoka; Vito Turk; Boris Turk (pp. 22-33).
Lysosomes are the key degradative compartments of the cell. Lysosomal cathepsins, which are enclosed in the lysosomes, help to maintain the homeostasis of the cell's metabolism by participating in the degradation of heterophagic and autophagic material. Following the targeted lysosomal membrane's destabilization, the cathepsins can be released into the cytosol and initiate the lysosomal pathway of apoptosis through the cleavage of Bid and the degradation of the anti-apoptotic Bcl-2 homologues. Cathepsins can also amplify the apoptotic signaling, when the lysosomal membranes are destabilized at a later stage of apoptosis, initiated by other stimuli. However, the functional integrity of the lysosomal compartment during apoptosis enables efficient autophagy, which can counteract apoptosis by providing the energy source and by disposing the damaged mitochondria, which generate the ROS. Impairing autophagy by disabling the lysosome function is being investigated as an adjuvant therapeutic approach to sensitize cells to apoptosis-inducing agents. Destabilization of the lysosomal membranes by the lysosomotropic detergents seems to be a promising strategy in this context as it would not only disable autophagy, but also promote apoptosis through the initiation of the lysosomal pathway. In contrast, the impaired autophagy and lysosomal degradation linked with the increased oxidative stress underlie degenerative changes in the aging neurons. This further suggests that lysosomes and lysosomal cathepsins have a dual role in cell death. This article is part of a Special Issue entitled: Proteolysis 50years after the discovery of lysosome.►Apoptotic pathways and the cathepsins, including granule-mediated cell death. ►Lysosomal cathepsins as effector molecules in the lysosomal pathway of apoptosis. ►Lysosomes and lysosomal cathepsins as amplifiers of apoptotic signaling. ►Antiapoptotic roles of cathepsins. ►Therapeutic perspectives of lysosome targeting.
Keywords: Lysosome; Cathepsin; Apoptosis; Cell death; Autophagy; Cancer
Lysosomes and lysosomal cathepsins in cell death by Urška Repnik; Veronika Stoka; Vito Turk; Boris Turk (pp. 22-33).
Lysosomes are the key degradative compartments of the cell. Lysosomal cathepsins, which are enclosed in the lysosomes, help to maintain the homeostasis of the cell's metabolism by participating in the degradation of heterophagic and autophagic material. Following the targeted lysosomal membrane's destabilization, the cathepsins can be released into the cytosol and initiate the lysosomal pathway of apoptosis through the cleavage of Bid and the degradation of the anti-apoptotic Bcl-2 homologues. Cathepsins can also amplify the apoptotic signaling, when the lysosomal membranes are destabilized at a later stage of apoptosis, initiated by other stimuli. However, the functional integrity of the lysosomal compartment during apoptosis enables efficient autophagy, which can counteract apoptosis by providing the energy source and by disposing the damaged mitochondria, which generate the ROS. Impairing autophagy by disabling the lysosome function is being investigated as an adjuvant therapeutic approach to sensitize cells to apoptosis-inducing agents. Destabilization of the lysosomal membranes by the lysosomotropic detergents seems to be a promising strategy in this context as it would not only disable autophagy, but also promote apoptosis through the initiation of the lysosomal pathway. In contrast, the impaired autophagy and lysosomal degradation linked with the increased oxidative stress underlie degenerative changes in the aging neurons. This further suggests that lysosomes and lysosomal cathepsins have a dual role in cell death. This article is part of a Special Issue entitled: Proteolysis 50years after the discovery of lysosome.►Apoptotic pathways and the cathepsins, including granule-mediated cell death. ►Lysosomal cathepsins as effector molecules in the lysosomal pathway of apoptosis. ►Lysosomes and lysosomal cathepsins as amplifiers of apoptotic signaling. ►Antiapoptotic roles of cathepsins. ►Therapeutic perspectives of lysosome targeting.
Keywords: Lysosome; Cathepsin; Apoptosis; Cell death; Autophagy; Cancer
Lysosomes and lysosomal cathepsins in cell death by Urška Repnik; Veronika Stoka; Vito Turk; Boris Turk (pp. 22-33).
Lysosomes are the key degradative compartments of the cell. Lysosomal cathepsins, which are enclosed in the lysosomes, help to maintain the homeostasis of the cell's metabolism by participating in the degradation of heterophagic and autophagic material. Following the targeted lysosomal membrane's destabilization, the cathepsins can be released into the cytosol and initiate the lysosomal pathway of apoptosis through the cleavage of Bid and the degradation of the anti-apoptotic Bcl-2 homologues. Cathepsins can also amplify the apoptotic signaling, when the lysosomal membranes are destabilized at a later stage of apoptosis, initiated by other stimuli. However, the functional integrity of the lysosomal compartment during apoptosis enables efficient autophagy, which can counteract apoptosis by providing the energy source and by disposing the damaged mitochondria, which generate the ROS. Impairing autophagy by disabling the lysosome function is being investigated as an adjuvant therapeutic approach to sensitize cells to apoptosis-inducing agents. Destabilization of the lysosomal membranes by the lysosomotropic detergents seems to be a promising strategy in this context as it would not only disable autophagy, but also promote apoptosis through the initiation of the lysosomal pathway. In contrast, the impaired autophagy and lysosomal degradation linked with the increased oxidative stress underlie degenerative changes in the aging neurons. This further suggests that lysosomes and lysosomal cathepsins have a dual role in cell death. This article is part of a Special Issue entitled: Proteolysis 50years after the discovery of lysosome.►Apoptotic pathways and the cathepsins, including granule-mediated cell death. ►Lysosomal cathepsins as effector molecules in the lysosomal pathway of apoptosis. ►Lysosomes and lysosomal cathepsins as amplifiers of apoptotic signaling. ►Antiapoptotic roles of cathepsins. ►Therapeutic perspectives of lysosome targeting.
Keywords: Lysosome; Cathepsin; Apoptosis; Cell death; Autophagy; Cancer
Specific functions of lysosomal proteases in endocytic and autophagic pathways by Muller Sabrina Müller; Dennemarker Julia Dennemärker; Thomas Reinheckel (pp. 34-43).
Endolysosomal vesicles form a highly dynamic multifunctional cellular compartment that contains multiple highly potent proteolytic enzymes. Originally these proteases have been assigned to cooperate solely in executing the unselective ‘bulk proteolysis’ within the acidic milieu of the lysosome. Although to some degree this notion still holds true, evidence is accumulating for specific and regulatory functions of individual ‘acidic’ proteases in many cellular processes linked to the endosomal/lysosomal compartment. Here we summarize and discuss the functions of individual endolysosomal proteases in such diverse processes as the termination of growth factor signaling, lipoprotein particle degradation, infection, antigen presentation, and autophagy. This article is part of a Special Issue entitled: Proteolysis 50years after the discovery of lysosome.► The acidic cellular compartment contains multiple potent proteolytic enzymes. ► Collectively, endolysosomal proteases are involved in general protein turnover. ► Single protease deficiencies cause specific defects in distinct cellular pathways.
Keywords: Protease; Autophagy; Endocytosis; Phagocytosis; Protein turnover
Specific functions of lysosomal proteases in endocytic and autophagic pathways by Muller Sabrina Müller; Dennemarker Julia Dennemärker; Thomas Reinheckel (pp. 34-43).
Endolysosomal vesicles form a highly dynamic multifunctional cellular compartment that contains multiple highly potent proteolytic enzymes. Originally these proteases have been assigned to cooperate solely in executing the unselective ‘bulk proteolysis’ within the acidic milieu of the lysosome. Although to some degree this notion still holds true, evidence is accumulating for specific and regulatory functions of individual ‘acidic’ proteases in many cellular processes linked to the endosomal/lysosomal compartment. Here we summarize and discuss the functions of individual endolysosomal proteases in such diverse processes as the termination of growth factor signaling, lipoprotein particle degradation, infection, antigen presentation, and autophagy. This article is part of a Special Issue entitled: Proteolysis 50years after the discovery of lysosome.► The acidic cellular compartment contains multiple potent proteolytic enzymes. ► Collectively, endolysosomal proteases are involved in general protein turnover. ► Single protease deficiencies cause specific defects in distinct cellular pathways.
Keywords: Protease; Autophagy; Endocytosis; Phagocytosis; Protein turnover
Specific functions of lysosomal proteases in endocytic and autophagic pathways by Muller Sabrina Müller; Dennemarker Julia Dennemärker; Thomas Reinheckel (pp. 34-43).
Endolysosomal vesicles form a highly dynamic multifunctional cellular compartment that contains multiple highly potent proteolytic enzymes. Originally these proteases have been assigned to cooperate solely in executing the unselective ‘bulk proteolysis’ within the acidic milieu of the lysosome. Although to some degree this notion still holds true, evidence is accumulating for specific and regulatory functions of individual ‘acidic’ proteases in many cellular processes linked to the endosomal/lysosomal compartment. Here we summarize and discuss the functions of individual endolysosomal proteases in such diverse processes as the termination of growth factor signaling, lipoprotein particle degradation, infection, antigen presentation, and autophagy. This article is part of a Special Issue entitled: Proteolysis 50years after the discovery of lysosome.► The acidic cellular compartment contains multiple potent proteolytic enzymes. ► Collectively, endolysosomal proteases are involved in general protein turnover. ► Single protease deficiencies cause specific defects in distinct cellular pathways.
Keywords: Protease; Autophagy; Endocytosis; Phagocytosis; Protein turnover
Proteases in autophagy by Vitaliy Kaminskyy; Boris Zhivotovsky (pp. 44-50).
Autophagy is a process involved in the proteolytic degradation of cellular macromolecules in lysosomes, which requires the activity of proteases, enzymes that hydrolyse peptide bonds and play a critical role in the initiation and execution of autophagy. Importantly, proteases also inhibit autophagy in certain cases. The initial steps of macroautophagy depend on the proteolytic processing of a particular protein, Atg8, by a cysteine protease, Atg4. This processing step is essential for conjugation of Atg8 with phosphatidylethanolamine and, subsequently, autophagosome formation. Lysosomal hydrolases, known as cathepsins, can be divided into several groups based on the catalitic residue in the active site, namely, cysteine, serine and aspartic cathepsins, which catalyse the cleavage of peptide bonds of autophagy substrates and, together with other factors, dispose of the autophagic flux. Whilst most cathepsins degrade autophagosomal content, some, such as cathepsin L, also degrade lysosomal membrane components, GABARAP-II and LC3-II. In contrast, cathepsin A, a serine protease, is involved in inhibition of chaperon-mediated autophagy through proteolytic processing of LAMP-2A. In addition, other families of calcium-dependent non-lysosomal cysteine proteases, such as calpains, and cysteine aspartate-specific proteases, such as caspases, may cleave autophagy-related proteins, negatively influencing the execution of autophagic processes. Here we discuss the current state of knowledge concerning protein degradation by autophagy and outline the role of proteases in autophagic processes. This article is part of a Special Issue entitled: Proteolysis 50years after the discovery of lysosome.
Keywords: Abbreviations; CMA; chaperon-mediated autophagy; LAMP-2A; lysosome-associated membrane protein type 2A; RIP; receptor interacting protein; SOD1; superoxide dismutase 1Proteases; Autophagy; Cathepsins; Calpains; Caspases
Proteases in autophagy by Vitaliy Kaminskyy; Boris Zhivotovsky (pp. 44-50).
Autophagy is a process involved in the proteolytic degradation of cellular macromolecules in lysosomes, which requires the activity of proteases, enzymes that hydrolyse peptide bonds and play a critical role in the initiation and execution of autophagy. Importantly, proteases also inhibit autophagy in certain cases. The initial steps of macroautophagy depend on the proteolytic processing of a particular protein, Atg8, by a cysteine protease, Atg4. This processing step is essential for conjugation of Atg8 with phosphatidylethanolamine and, subsequently, autophagosome formation. Lysosomal hydrolases, known as cathepsins, can be divided into several groups based on the catalitic residue in the active site, namely, cysteine, serine and aspartic cathepsins, which catalyse the cleavage of peptide bonds of autophagy substrates and, together with other factors, dispose of the autophagic flux. Whilst most cathepsins degrade autophagosomal content, some, such as cathepsin L, also degrade lysosomal membrane components, GABARAP-II and LC3-II. In contrast, cathepsin A, a serine protease, is involved in inhibition of chaperon-mediated autophagy through proteolytic processing of LAMP-2A. In addition, other families of calcium-dependent non-lysosomal cysteine proteases, such as calpains, and cysteine aspartate-specific proteases, such as caspases, may cleave autophagy-related proteins, negatively influencing the execution of autophagic processes. Here we discuss the current state of knowledge concerning protein degradation by autophagy and outline the role of proteases in autophagic processes. This article is part of a Special Issue entitled: Proteolysis 50years after the discovery of lysosome.
Keywords: Abbreviations; CMA; chaperon-mediated autophagy; LAMP-2A; lysosome-associated membrane protein type 2A; RIP; receptor interacting protein; SOD1; superoxide dismutase 1Proteases; Autophagy; Cathepsins; Calpains; Caspases
Proteases in autophagy by Vitaliy Kaminskyy; Boris Zhivotovsky (pp. 44-50).
Autophagy is a process involved in the proteolytic degradation of cellular macromolecules in lysosomes, which requires the activity of proteases, enzymes that hydrolyse peptide bonds and play a critical role in the initiation and execution of autophagy. Importantly, proteases also inhibit autophagy in certain cases. The initial steps of macroautophagy depend on the proteolytic processing of a particular protein, Atg8, by a cysteine protease, Atg4. This processing step is essential for conjugation of Atg8 with phosphatidylethanolamine and, subsequently, autophagosome formation. Lysosomal hydrolases, known as cathepsins, can be divided into several groups based on the catalitic residue in the active site, namely, cysteine, serine and aspartic cathepsins, which catalyse the cleavage of peptide bonds of autophagy substrates and, together with other factors, dispose of the autophagic flux. Whilst most cathepsins degrade autophagosomal content, some, such as cathepsin L, also degrade lysosomal membrane components, GABARAP-II and LC3-II. In contrast, cathepsin A, a serine protease, is involved in inhibition of chaperon-mediated autophagy through proteolytic processing of LAMP-2A. In addition, other families of calcium-dependent non-lysosomal cysteine proteases, such as calpains, and cysteine aspartate-specific proteases, such as caspases, may cleave autophagy-related proteins, negatively influencing the execution of autophagic processes. Here we discuss the current state of knowledge concerning protein degradation by autophagy and outline the role of proteases in autophagic processes. This article is part of a Special Issue entitled: Proteolysis 50years after the discovery of lysosome.
Keywords: Abbreviations; CMA; chaperon-mediated autophagy; LAMP-2A; lysosome-associated membrane protein type 2A; RIP; receptor interacting protein; SOD1; superoxide dismutase 1Proteases; Autophagy; Cathepsins; Calpains; Caspases
Metabolic contribution of hepatic autophagic proteolysis: Old wine in new bottles by Takashi Ueno; Junji Ezaki; Eiki Kominami (pp. 51-58).
Pioneering work on autophagy was achieved soon after the discovery of lysosomes more than 50years ago. Due to its prominent lysosomal activity and technical ease of handling, the liver has been at the center of continuous and vigorous investigations into autophagy. Many important discoveries, including suppression by insulin and plasma amino acids and stimulation by glucagon, have been made through in vivo and in vitro studies using perfused liver and cultured hepatocytes. The long-term controversy about the origin and nature of the autophagosome membrane has finally led to the conclusion of “phagophore,” through extensive molecular cell biological approaches enlightened by the discovery of autophagy-essential ATG genes. Furthermore, recent studies using liver-specific autophagy-deficient mice have thrown light on the unique role of a selective substrate of autophagy, p62. The stabilized p62 accumulating in autophagy-deficient liver manipulates Nrf2-dependent transcription activation through specific binding to Keap1, which results in the elevated gene expression involved in detoxification. This is the first example of the dysregulation of gene expression under autophagy deficiency. Thus, basal liver autophagy makes a large contribution to the maintenance of cell homeostasis and health. Meanwhile, precise comparisons of wild-type and liver-specific autophagy-deficient mice under starvation conditions have revealed that amino acids released by autophagic degradation can be metabolized to produce glucose via gluconeogenesis for the maintenance of blood glucose, and can also be excreted to the circulation to supply serum amino acids. These results strongly confirm that induced liver autophagy plays a pivotal role in metabolic compensation. This article is part of a Special Issue entitled: Proteolysis 50years after the discovery of lysosome.►The liver has been at the center of extensive investigations into autophagy. ►Induction mechanism and suppression by insulin and amino acids have been elucidated. ►Liver autophagy deficiency causes a p62-dependent dysregulation of gene expression. ►Amino acids released during liver autophagy contribute to maintaining blood glucose.
Keywords: Autophagy; Lysosome; Liver; p62; Amino acid; Gluconeogenesis
Metabolic contribution of hepatic autophagic proteolysis: Old wine in new bottles by Takashi Ueno; Junji Ezaki; Eiki Kominami (pp. 51-58).
Pioneering work on autophagy was achieved soon after the discovery of lysosomes more than 50years ago. Due to its prominent lysosomal activity and technical ease of handling, the liver has been at the center of continuous and vigorous investigations into autophagy. Many important discoveries, including suppression by insulin and plasma amino acids and stimulation by glucagon, have been made through in vivo and in vitro studies using perfused liver and cultured hepatocytes. The long-term controversy about the origin and nature of the autophagosome membrane has finally led to the conclusion of “phagophore,” through extensive molecular cell biological approaches enlightened by the discovery of autophagy-essential ATG genes. Furthermore, recent studies using liver-specific autophagy-deficient mice have thrown light on the unique role of a selective substrate of autophagy, p62. The stabilized p62 accumulating in autophagy-deficient liver manipulates Nrf2-dependent transcription activation through specific binding to Keap1, which results in the elevated gene expression involved in detoxification. This is the first example of the dysregulation of gene expression under autophagy deficiency. Thus, basal liver autophagy makes a large contribution to the maintenance of cell homeostasis and health. Meanwhile, precise comparisons of wild-type and liver-specific autophagy-deficient mice under starvation conditions have revealed that amino acids released by autophagic degradation can be metabolized to produce glucose via gluconeogenesis for the maintenance of blood glucose, and can also be excreted to the circulation to supply serum amino acids. These results strongly confirm that induced liver autophagy plays a pivotal role in metabolic compensation. This article is part of a Special Issue entitled: Proteolysis 50years after the discovery of lysosome.►The liver has been at the center of extensive investigations into autophagy. ►Induction mechanism and suppression by insulin and amino acids have been elucidated. ►Liver autophagy deficiency causes a p62-dependent dysregulation of gene expression. ►Amino acids released during liver autophagy contribute to maintaining blood glucose.
Keywords: Autophagy; Lysosome; Liver; p62; Amino acid; Gluconeogenesis
Metabolic contribution of hepatic autophagic proteolysis: Old wine in new bottles by Takashi Ueno; Junji Ezaki; Eiki Kominami (pp. 51-58).
Pioneering work on autophagy was achieved soon after the discovery of lysosomes more than 50years ago. Due to its prominent lysosomal activity and technical ease of handling, the liver has been at the center of continuous and vigorous investigations into autophagy. Many important discoveries, including suppression by insulin and plasma amino acids and stimulation by glucagon, have been made through in vivo and in vitro studies using perfused liver and cultured hepatocytes. The long-term controversy about the origin and nature of the autophagosome membrane has finally led to the conclusion of “phagophore,” through extensive molecular cell biological approaches enlightened by the discovery of autophagy-essential ATG genes. Furthermore, recent studies using liver-specific autophagy-deficient mice have thrown light on the unique role of a selective substrate of autophagy, p62. The stabilized p62 accumulating in autophagy-deficient liver manipulates Nrf2-dependent transcription activation through specific binding to Keap1, which results in the elevated gene expression involved in detoxification. This is the first example of the dysregulation of gene expression under autophagy deficiency. Thus, basal liver autophagy makes a large contribution to the maintenance of cell homeostasis and health. Meanwhile, precise comparisons of wild-type and liver-specific autophagy-deficient mice under starvation conditions have revealed that amino acids released by autophagic degradation can be metabolized to produce glucose via gluconeogenesis for the maintenance of blood glucose, and can also be excreted to the circulation to supply serum amino acids. These results strongly confirm that induced liver autophagy plays a pivotal role in metabolic compensation. This article is part of a Special Issue entitled: Proteolysis 50years after the discovery of lysosome.►The liver has been at the center of extensive investigations into autophagy. ►Induction mechanism and suppression by insulin and amino acids have been elucidated. ►Liver autophagy deficiency causes a p62-dependent dysregulation of gene expression. ►Amino acids released during liver autophagy contribute to maintaining blood glucose.
Keywords: Autophagy; Lysosome; Liver; p62; Amino acid; Gluconeogenesis
Intercellular communication via the endo-lysosomal system: Translocation of granzymes through membrane barriers by Sarah E. Stewart; Michael E. D'Angelo; Phillip I. Bird (pp. 59-67).
Cytotoxic lymphocytes (CLs) are responsible for the clearance of virally infected or neoplastic cells. CLs possess specialised lysosome-related organelles called granules which contain the granzyme family of serine proteases and perforin. Granzymes may induce apoptosis in the target cell when delivered by the pore forming protein, perforin. Here we follow the perforin-granzyme pathway from synthesis and storage in the granule, to exocytosis and finally delivery into the target cell. This review focuses on the controversial subject of perforin-mediated translocation of granzymes into the target cell cytoplasm. It remains unclear whether this occurs at the cell surface with granzymes moving through a perforin pore in the plasma membrane, or if it involves internalisation of perforin and granzymes and subsequent release from an endocytic compartment. The latter mechanism would represent an example of cross talk between the endo-lysosomal pathways of individual cells. This article is part of a Special Issue entitled: Proteolysis 50years after the discovery of lysosome.► Delivery of granzymes by perforin is not understood. ► The two models for delivery do not explain all the experimental data. ► This review highlights the major questions that remain in this field.
Keywords: Abbreviations; CL; Cytotoxic lymphocyte; NK; natural killer cell; CTL; cytolytic T lymphocyte; LAMP; lysosomal associated membrane protein; ER; endoplasmic reticulum; GAG; glycosaminoglycan; SNARE; n-ethylmaleimide-sensitive factor attachment protein receptor; GrB; Granzyme B; PI; propidium iodide; TEM; transmission electron microscopy; FHL2; familial haemophagocytic lymphohistiocytosis 2; MAC; membrane attack complex; c9; ninth complement component; CDC; cholesterol-dependent cytolysin; CH; cluster of helices; TMH; transmembrane helices; PLY; pneumolysin; PFO; perfringolysin O; SLO; streptolysin O; HEG; human erythrocyte ghost; FITC; fluorescein isothiocyanate; GUV; giant unilamellar vesicle; HPTS; 8-hydroxypyrene-1,3,6-trisulfonic acid; CI-MPR; cation-independent mannose-6-phosphate receptor; EEA1; early endosomal antigen 1; MBV; multi-vesicular body; AD; adenovirus; CCP; clathrin coated pitPerforin; Granzyme; Cytotoxic lymphocyte; Endocytosis; Pore; Membrane repair response
Intercellular communication via the endo-lysosomal system: Translocation of granzymes through membrane barriers by Sarah E. Stewart; Michael E. D'Angelo; Phillip I. Bird (pp. 59-67).
Cytotoxic lymphocytes (CLs) are responsible for the clearance of virally infected or neoplastic cells. CLs possess specialised lysosome-related organelles called granules which contain the granzyme family of serine proteases and perforin. Granzymes may induce apoptosis in the target cell when delivered by the pore forming protein, perforin. Here we follow the perforin-granzyme pathway from synthesis and storage in the granule, to exocytosis and finally delivery into the target cell. This review focuses on the controversial subject of perforin-mediated translocation of granzymes into the target cell cytoplasm. It remains unclear whether this occurs at the cell surface with granzymes moving through a perforin pore in the plasma membrane, or if it involves internalisation of perforin and granzymes and subsequent release from an endocytic compartment. The latter mechanism would represent an example of cross talk between the endo-lysosomal pathways of individual cells. This article is part of a Special Issue entitled: Proteolysis 50years after the discovery of lysosome.► Delivery of granzymes by perforin is not understood. ► The two models for delivery do not explain all the experimental data. ► This review highlights the major questions that remain in this field.
Keywords: Abbreviations; CL; Cytotoxic lymphocyte; NK; natural killer cell; CTL; cytolytic T lymphocyte; LAMP; lysosomal associated membrane protein; ER; endoplasmic reticulum; GAG; glycosaminoglycan; SNARE; n-ethylmaleimide-sensitive factor attachment protein receptor; GrB; Granzyme B; PI; propidium iodide; TEM; transmission electron microscopy; FHL2; familial haemophagocytic lymphohistiocytosis 2; MAC; membrane attack complex; c9; ninth complement component; CDC; cholesterol-dependent cytolysin; CH; cluster of helices; TMH; transmembrane helices; PLY; pneumolysin; PFO; perfringolysin O; SLO; streptolysin O; HEG; human erythrocyte ghost; FITC; fluorescein isothiocyanate; GUV; giant unilamellar vesicle; HPTS; 8-hydroxypyrene-1,3,6-trisulfonic acid; CI-MPR; cation-independent mannose-6-phosphate receptor; EEA1; early endosomal antigen 1; MBV; multi-vesicular body; AD; adenovirus; CCP; clathrin coated pitPerforin; Granzyme; Cytotoxic lymphocyte; Endocytosis; Pore; Membrane repair response
Intercellular communication via the endo-lysosomal system: Translocation of granzymes through membrane barriers by Sarah E. Stewart; Michael E. D'Angelo; Phillip I. Bird (pp. 59-67).
Cytotoxic lymphocytes (CLs) are responsible for the clearance of virally infected or neoplastic cells. CLs possess specialised lysosome-related organelles called granules which contain the granzyme family of serine proteases and perforin. Granzymes may induce apoptosis in the target cell when delivered by the pore forming protein, perforin. Here we follow the perforin-granzyme pathway from synthesis and storage in the granule, to exocytosis and finally delivery into the target cell. This review focuses on the controversial subject of perforin-mediated translocation of granzymes into the target cell cytoplasm. It remains unclear whether this occurs at the cell surface with granzymes moving through a perforin pore in the plasma membrane, or if it involves internalisation of perforin and granzymes and subsequent release from an endocytic compartment. The latter mechanism would represent an example of cross talk between the endo-lysosomal pathways of individual cells. This article is part of a Special Issue entitled: Proteolysis 50years after the discovery of lysosome.► Delivery of granzymes by perforin is not understood. ► The two models for delivery do not explain all the experimental data. ► This review highlights the major questions that remain in this field.
Keywords: Abbreviations; CL; Cytotoxic lymphocyte; NK; natural killer cell; CTL; cytolytic T lymphocyte; LAMP; lysosomal associated membrane protein; ER; endoplasmic reticulum; GAG; glycosaminoglycan; SNARE; n-ethylmaleimide-sensitive factor attachment protein receptor; GrB; Granzyme B; PI; propidium iodide; TEM; transmission electron microscopy; FHL2; familial haemophagocytic lymphohistiocytosis 2; MAC; membrane attack complex; c9; ninth complement component; CDC; cholesterol-dependent cytolysin; CH; cluster of helices; TMH; transmembrane helices; PLY; pneumolysin; PFO; perfringolysin O; SLO; streptolysin O; HEG; human erythrocyte ghost; FITC; fluorescein isothiocyanate; GUV; giant unilamellar vesicle; HPTS; 8-hydroxypyrene-1,3,6-trisulfonic acid; CI-MPR; cation-independent mannose-6-phosphate receptor; EEA1; early endosomal antigen 1; MBV; multi-vesicular body; AD; adenovirus; CCP; clathrin coated pitPerforin; Granzyme; Cytotoxic lymphocyte; Endocytosis; Pore; Membrane repair response
Cysteine cathepsins: From structure, function and regulation to new frontiers by Vito Turk; Veronika Stoka; Olga Vasiljeva; Miha Renko; Tao Sun; Boris Turk; Dušan Turk (pp. 68-88).
It is more than 50years since the lysosome was discovered. Since then its hydrolytic machinery, including proteases and other hydrolases, has been fairly well identified and characterized. Among these are the cysteine cathepsins, members of the family of papain-like cysteine proteases. They have unique reactive-site properties and an uneven tissue-specific expression pattern. In living organisms their activity is a delicate balance of expression, targeting, zymogen activation, inhibition by protein inhibitors and degradation. The specificity of their substrate binding sites, small-molecule inhibitor repertoire and crystal structures are providing new tools for research and development. Their unique reactive-site properties have made it possible to confine the targets simply by the use of appropriate reactive groups. The epoxysuccinyls still dominate the field, but now nitriles seem to be the most appropriate “warhead”. The view of cysteine cathepsins as lysosomal proteases is changing as there is now clear evidence of their localization in other cellular compartments. Besides being involved in protein turnover, they build an important part of the endosomal antigen presentation. Together with the growing number of non-endosomal roles of cysteine cathepsins is growing also the knowledge of their involvement in diseases such as cancer and rheumatoid arthritis, among others. Finally, cysteine cathepsins are important regulators and signaling molecules of an unimaginable number of biological processes. The current challenge is to identify their endogenous substrates, in order to gain an insight into the mechanisms of substrate degradation and processing. In this review, some of the remarkable advances that have taken place in the past decade are presented. This article is part of a Special Issue entitled: Proteolysis 50years after the discovery of lysosome.► Current advances in the field of cysteine cathepsins and their regulation. ► Cysteine cathepsin activity as a delicate balance of various factors. ► Structure of cysteine cathepsins and their mechanism of interaction with inhibitors. ► Inhibition of cysteine cathepsins by protein and small-molecule inhibitors. ► The increased expression of cysteine cathepsins implicated in various diseases.
Keywords: Cysteine cathepsin; Protein inhibitor; Cystatin; Small-molecule inhibitor; Mechanism of interaction; Biological function
Cysteine cathepsins: From structure, function and regulation to new frontiers by Vito Turk; Veronika Stoka; Olga Vasiljeva; Miha Renko; Tao Sun; Boris Turk; Dušan Turk (pp. 68-88).
It is more than 50years since the lysosome was discovered. Since then its hydrolytic machinery, including proteases and other hydrolases, has been fairly well identified and characterized. Among these are the cysteine cathepsins, members of the family of papain-like cysteine proteases. They have unique reactive-site properties and an uneven tissue-specific expression pattern. In living organisms their activity is a delicate balance of expression, targeting, zymogen activation, inhibition by protein inhibitors and degradation. The specificity of their substrate binding sites, small-molecule inhibitor repertoire and crystal structures are providing new tools for research and development. Their unique reactive-site properties have made it possible to confine the targets simply by the use of appropriate reactive groups. The epoxysuccinyls still dominate the field, but now nitriles seem to be the most appropriate “warhead”. The view of cysteine cathepsins as lysosomal proteases is changing as there is now clear evidence of their localization in other cellular compartments. Besides being involved in protein turnover, they build an important part of the endosomal antigen presentation. Together with the growing number of non-endosomal roles of cysteine cathepsins is growing also the knowledge of their involvement in diseases such as cancer and rheumatoid arthritis, among others. Finally, cysteine cathepsins are important regulators and signaling molecules of an unimaginable number of biological processes. The current challenge is to identify their endogenous substrates, in order to gain an insight into the mechanisms of substrate degradation and processing. In this review, some of the remarkable advances that have taken place in the past decade are presented. This article is part of a Special Issue entitled: Proteolysis 50years after the discovery of lysosome.► Current advances in the field of cysteine cathepsins and their regulation. ► Cysteine cathepsin activity as a delicate balance of various factors. ► Structure of cysteine cathepsins and their mechanism of interaction with inhibitors. ► Inhibition of cysteine cathepsins by protein and small-molecule inhibitors. ► The increased expression of cysteine cathepsins implicated in various diseases.
Keywords: Cysteine cathepsin; Protein inhibitor; Cystatin; Small-molecule inhibitor; Mechanism of interaction; Biological function
Cysteine cathepsins: From structure, function and regulation to new frontiers by Vito Turk; Veronika Stoka; Olga Vasiljeva; Miha Renko; Tao Sun; Boris Turk; Dušan Turk (pp. 68-88).
It is more than 50years since the lysosome was discovered. Since then its hydrolytic machinery, including proteases and other hydrolases, has been fairly well identified and characterized. Among these are the cysteine cathepsins, members of the family of papain-like cysteine proteases. They have unique reactive-site properties and an uneven tissue-specific expression pattern. In living organisms their activity is a delicate balance of expression, targeting, zymogen activation, inhibition by protein inhibitors and degradation. The specificity of their substrate binding sites, small-molecule inhibitor repertoire and crystal structures are providing new tools for research and development. Their unique reactive-site properties have made it possible to confine the targets simply by the use of appropriate reactive groups. The epoxysuccinyls still dominate the field, but now nitriles seem to be the most appropriate “warhead”. The view of cysteine cathepsins as lysosomal proteases is changing as there is now clear evidence of their localization in other cellular compartments. Besides being involved in protein turnover, they build an important part of the endosomal antigen presentation. Together with the growing number of non-endosomal roles of cysteine cathepsins is growing also the knowledge of their involvement in diseases such as cancer and rheumatoid arthritis, among others. Finally, cysteine cathepsins are important regulators and signaling molecules of an unimaginable number of biological processes. The current challenge is to identify their endogenous substrates, in order to gain an insight into the mechanisms of substrate degradation and processing. In this review, some of the remarkable advances that have taken place in the past decade are presented. This article is part of a Special Issue entitled: Proteolysis 50years after the discovery of lysosome.► Current advances in the field of cysteine cathepsins and their regulation. ► Cysteine cathepsin activity as a delicate balance of various factors. ► Structure of cysteine cathepsins and their mechanism of interaction with inhibitors. ► Inhibition of cysteine cathepsins by protein and small-molecule inhibitors. ► The increased expression of cysteine cathepsins implicated in various diseases.
Keywords: Cysteine cathepsin; Protein inhibitor; Cystatin; Small-molecule inhibitor; Mechanism of interaction; Biological function
Cysteine Cathepsins in the secretory vesicle produce active peptides: Cathepsin L generates peptide neurotransmitters and cathepsin B produces beta-amyloid of Alzheimer's disease by Vivian Hook; Lydiane Funkelstein; Jill Wegrzyn; Steven Bark; Mark Kindy; Gregory Hook (pp. 89-104).
Recent new findings indicate significant biological roles of cysteine cathepsin proteases in secretory vesicles for production of biologically active peptides. Notably, cathepsin L in secretory vesicles functions as a key protease for proteolytic processing of proneuropeptides (and prohormones) into active neuropeptides that are released to mediate cell–cell communication in the nervous system for neurotransmission. Moreover, cathepsin B in secretory vesicles has been recently identified as a β-secretase for production of neurotoxic β- amyloid (Aβ) peptides that accumulate in Alzheimer's disease (AD), participating as a notable factor in the severe memory loss in AD. These secretory vesicle functions of cathepsins L and B for production of biologically active peptides contrast with the well-known role of cathepsin proteases in lysosomes for the degradation of proteins to result in their inactivation. The unique secretory vesicle proteome indicates proteins of distinct functional categories that provide the intravesicular environment for support of cysteine cathepsin functions. Features of the secretory vesicle protein systems insure optimized intravesicular conditions that support the proteolytic activity of cathepsins. These new findings of recently discovered biological roles of cathepsins L and B indicate their significance in human health and disease. This article is part of a Special Issue entitled: Proteolysis 50years after the discovery of lysosome.► Cathepsin L in secretory vesicles participates in the biosynthesis of peptide neurotransmitters and hormones. ► Cathepsin B produces neurotoxic β-amyloid in secretory vesicles and represents a new drug target for Alzheimer's disease. ► The secretory vesicle proteome indicates the protein environment that supports cathepsins L and B in the production of active peptides. ► Cysteine cathepsins possess novel biological functions in secretory vesicles for health and disease.
Keywords: Cathepsin L; Cathepsin B; Secretory vesicle; Peptide neurotransmitters; β-amyloid; Alzheimer's disease
Cysteine Cathepsins in the secretory vesicle produce active peptides: Cathepsin L generates peptide neurotransmitters and cathepsin B produces beta-amyloid of Alzheimer's disease by Vivian Hook; Lydiane Funkelstein; Jill Wegrzyn; Steven Bark; Mark Kindy; Gregory Hook (pp. 89-104).
Recent new findings indicate significant biological roles of cysteine cathepsin proteases in secretory vesicles for production of biologically active peptides. Notably, cathepsin L in secretory vesicles functions as a key protease for proteolytic processing of proneuropeptides (and prohormones) into active neuropeptides that are released to mediate cell–cell communication in the nervous system for neurotransmission. Moreover, cathepsin B in secretory vesicles has been recently identified as a β-secretase for production of neurotoxic β- amyloid (Aβ) peptides that accumulate in Alzheimer's disease (AD), participating as a notable factor in the severe memory loss in AD. These secretory vesicle functions of cathepsins L and B for production of biologically active peptides contrast with the well-known role of cathepsin proteases in lysosomes for the degradation of proteins to result in their inactivation. The unique secretory vesicle proteome indicates proteins of distinct functional categories that provide the intravesicular environment for support of cysteine cathepsin functions. Features of the secretory vesicle protein systems insure optimized intravesicular conditions that support the proteolytic activity of cathepsins. These new findings of recently discovered biological roles of cathepsins L and B indicate their significance in human health and disease. This article is part of a Special Issue entitled: Proteolysis 50years after the discovery of lysosome.► Cathepsin L in secretory vesicles participates in the biosynthesis of peptide neurotransmitters and hormones. ► Cathepsin B produces neurotoxic β-amyloid in secretory vesicles and represents a new drug target for Alzheimer's disease. ► The secretory vesicle proteome indicates the protein environment that supports cathepsins L and B in the production of active peptides. ► Cysteine cathepsins possess novel biological functions in secretory vesicles for health and disease.
Keywords: Cathepsin L; Cathepsin B; Secretory vesicle; Peptide neurotransmitters; β-amyloid; Alzheimer's disease
Cysteine Cathepsins in the secretory vesicle produce active peptides: Cathepsin L generates peptide neurotransmitters and cathepsin B produces beta-amyloid of Alzheimer's disease by Vivian Hook; Lydiane Funkelstein; Jill Wegrzyn; Steven Bark; Mark Kindy; Gregory Hook (pp. 89-104).
Recent new findings indicate significant biological roles of cysteine cathepsin proteases in secretory vesicles for production of biologically active peptides. Notably, cathepsin L in secretory vesicles functions as a key protease for proteolytic processing of proneuropeptides (and prohormones) into active neuropeptides that are released to mediate cell–cell communication in the nervous system for neurotransmission. Moreover, cathepsin B in secretory vesicles has been recently identified as a β-secretase for production of neurotoxic β- amyloid (Aβ) peptides that accumulate in Alzheimer's disease (AD), participating as a notable factor in the severe memory loss in AD. These secretory vesicle functions of cathepsins L and B for production of biologically active peptides contrast with the well-known role of cathepsin proteases in lysosomes for the degradation of proteins to result in their inactivation. The unique secretory vesicle proteome indicates proteins of distinct functional categories that provide the intravesicular environment for support of cysteine cathepsin functions. Features of the secretory vesicle protein systems insure optimized intravesicular conditions that support the proteolytic activity of cathepsins. These new findings of recently discovered biological roles of cathepsins L and B indicate their significance in human health and disease. This article is part of a Special Issue entitled: Proteolysis 50years after the discovery of lysosome.► Cathepsin L in secretory vesicles participates in the biosynthesis of peptide neurotransmitters and hormones. ► Cathepsin B produces neurotoxic β-amyloid in secretory vesicles and represents a new drug target for Alzheimer's disease. ► The secretory vesicle proteome indicates the protein environment that supports cathepsins L and B in the production of active peptides. ► Cysteine cathepsins possess novel biological functions in secretory vesicles for health and disease.
Keywords: Cathepsin L; Cathepsin B; Secretory vesicle; Peptide neurotransmitters; β-amyloid; Alzheimer's disease
Emerging roles of cathepsin E in host defense mechanisms by Kenji Yamamoto; Tomoyo Kawakubo; Atsushi Yasukochi; Takayuki Tsukuba (pp. 105-112).
Cathepsin E is an intracellular aspartic proteinase of the pepsin superfamily, which is predominantly expressed in certain cell types, including the immune system cells and rapidly regenerating gastric mucosal and epidermal keratinocytes. The intracellular localization of this protein varies with different cell types. The endosomal localization is primarily found in antigen-presenting cells and gastric cells. The membrane association is observed with certain cell types such as erythrocytes, osteoclasts, gastric parietal cells and renal proximal tubule cells. This enzyme is also found in the endoplasmic reticulum, Golgi complex and cytosolic compartments in various cell types. In addition to its intracellular localization, cathepsin E occurs in the culture medium of activated phagocytes and cancer cells as the catalytically active enzyme. Its strategic expression and localization thus suggests the association of this enzyme with specific biological functions of the individual cell types. Recent genetic and pharmacological studies have particularly suggested that cathepsin E plays an important role in host defense against cancer cells and invading microorganisms. This review focuses emerging roles of cathepsin E in immune system cells and skin keratinocytes, and in host defense against cancer cells. This article is part of a Special Issue entitled: Proteolysis 50 years after the discovery of lysosome.► This review focuses emerging roles of cathepsin E in host defense mechanisms. ► Cathepsin E differentially regulates the nature and functions of macrophages and DCs. ► Cathepsin E has an antitumorigenic activity by multiple mechanisms. ► Cathepsin E is involved in keratinocyte terminal differentiation.
Keywords: Cathepsin E; Aspartic proteinase; Cancer; Epidermal differentiation; Peptide-mimetic inhibitor and activator
Emerging roles of cathepsin E in host defense mechanisms by Kenji Yamamoto; Tomoyo Kawakubo; Atsushi Yasukochi; Takayuki Tsukuba (pp. 105-112).
Cathepsin E is an intracellular aspartic proteinase of the pepsin superfamily, which is predominantly expressed in certain cell types, including the immune system cells and rapidly regenerating gastric mucosal and epidermal keratinocytes. The intracellular localization of this protein varies with different cell types. The endosomal localization is primarily found in antigen-presenting cells and gastric cells. The membrane association is observed with certain cell types such as erythrocytes, osteoclasts, gastric parietal cells and renal proximal tubule cells. This enzyme is also found in the endoplasmic reticulum, Golgi complex and cytosolic compartments in various cell types. In addition to its intracellular localization, cathepsin E occurs in the culture medium of activated phagocytes and cancer cells as the catalytically active enzyme. Its strategic expression and localization thus suggests the association of this enzyme with specific biological functions of the individual cell types. Recent genetic and pharmacological studies have particularly suggested that cathepsin E plays an important role in host defense against cancer cells and invading microorganisms. This review focuses emerging roles of cathepsin E in immune system cells and skin keratinocytes, and in host defense against cancer cells. This article is part of a Special Issue entitled: Proteolysis 50 years after the discovery of lysosome.► This review focuses emerging roles of cathepsin E in host defense mechanisms. ► Cathepsin E differentially regulates the nature and functions of macrophages and DCs. ► Cathepsin E has an antitumorigenic activity by multiple mechanisms. ► Cathepsin E is involved in keratinocyte terminal differentiation.
Keywords: Cathepsin E; Aspartic proteinase; Cancer; Epidermal differentiation; Peptide-mimetic inhibitor and activator
Emerging roles of cathepsin E in host defense mechanisms by Kenji Yamamoto; Tomoyo Kawakubo; Atsushi Yasukochi; Takayuki Tsukuba (pp. 105-112).
Cathepsin E is an intracellular aspartic proteinase of the pepsin superfamily, which is predominantly expressed in certain cell types, including the immune system cells and rapidly regenerating gastric mucosal and epidermal keratinocytes. The intracellular localization of this protein varies with different cell types. The endosomal localization is primarily found in antigen-presenting cells and gastric cells. The membrane association is observed with certain cell types such as erythrocytes, osteoclasts, gastric parietal cells and renal proximal tubule cells. This enzyme is also found in the endoplasmic reticulum, Golgi complex and cytosolic compartments in various cell types. In addition to its intracellular localization, cathepsin E occurs in the culture medium of activated phagocytes and cancer cells as the catalytically active enzyme. Its strategic expression and localization thus suggests the association of this enzyme with specific biological functions of the individual cell types. Recent genetic and pharmacological studies have particularly suggested that cathepsin E plays an important role in host defense against cancer cells and invading microorganisms. This review focuses emerging roles of cathepsin E in immune system cells and skin keratinocytes, and in host defense against cancer cells. This article is part of a Special Issue entitled: Proteolysis 50 years after the discovery of lysosome.► This review focuses emerging roles of cathepsin E in host defense mechanisms. ► Cathepsin E differentially regulates the nature and functions of macrophages and DCs. ► Cathepsin E has an antitumorigenic activity by multiple mechanisms. ► Cathepsin E is involved in keratinocyte terminal differentiation.
Keywords: Cathepsin E; Aspartic proteinase; Cancer; Epidermal differentiation; Peptide-mimetic inhibitor and activator
Proliferative versus apoptotic functions of caspase-8 by Bram J. van Raam; Guy S. Salvesen (pp. 113-122).
Caspase-8, the initiator of extrinsically-triggered apoptosis, also has important functions in cellular activation and differentiation downstream of a variety of cell surface receptors. It has become increasingly clear that the heterodimer of caspase-8 with the long isoform of cellular FLIP (FLIPL) fulfills these pro-survival functions of caspase-8. FLIPL, a catalytically defective caspase-8 paralog, can interact with caspase-8 to activate its catalytic function. The caspase-8/FLIPL heterodimer has a restricted substrate repertoire and does not induce apoptosis. In essence, caspase-8 heterodimerized with FLIPL prevents the receptor interacting kinases RIPK1 and -3 from executing the form of cell death known as necroptosis. This review discusses the latest insights in caspase-8 homo- versus heterodimerization and the implication this has for cellular death or survival. This article is part of a Special Issue entitled: Proteolysis 50 years after the discovery of lysosome.Display Omitted► We discuss the emerging role of the caspase-8 in cellular survival and activation. ► Caspase-8 homodimer is pro-apoptotic; the heterodimer with FLIPL is pro-survival. ► Control of RIPK1 activity is an essential function of caspase-8. ► Heterodimer in complex with FADD and RIPK1 activates NF-κB, only if FLIPL is cleaved. ► Further cleavage of the caspase-8 inter-subunit linker turns the heterodimer pro-apoptotic.
Keywords: Abbreviations; ALPS; acute lympho-proliferative syndrome; CARD; caspase recruitment domain; CED; Caenorhabditis elegans; death protein; DD; death domain; DED; death effector domain; DISC; death inducing signaling complex; DR; death receptor; FADD; Fas-associated death domain protein; FLIP; FLICE inhibitory protein; HDAC; histone deacetylase; ICE; interleukin converting enzyme; IL; interleukin; IRF; interferon regulatory factor; JNK; c-Jun N-terminal kinase; NEMO; NF-κB essential modulator; NF; nuclear factor; RIPK; receptor interacting protein kinase; ROS; reactive oxygen species; TNF; tumor necrosis factor; TNFR; TNF receptor; TRADD; TNFR associated death domain protein; TRAF; TNFR associated factor; TWEAK; TNF-related weak inducer of apoptosisApoptosis; Caspase; FLIP; Necroptosis; Receptor interacting protein kinase
Proliferative versus apoptotic functions of caspase-8 by Bram J. van Raam; Guy S. Salvesen (pp. 113-122).
Caspase-8, the initiator of extrinsically-triggered apoptosis, also has important functions in cellular activation and differentiation downstream of a variety of cell surface receptors. It has become increasingly clear that the heterodimer of caspase-8 with the long isoform of cellular FLIP (FLIPL) fulfills these pro-survival functions of caspase-8. FLIPL, a catalytically defective caspase-8 paralog, can interact with caspase-8 to activate its catalytic function. The caspase-8/FLIPL heterodimer has a restricted substrate repertoire and does not induce apoptosis. In essence, caspase-8 heterodimerized with FLIPL prevents the receptor interacting kinases RIPK1 and -3 from executing the form of cell death known as necroptosis. This review discusses the latest insights in caspase-8 homo- versus heterodimerization and the implication this has for cellular death or survival. This article is part of a Special Issue entitled: Proteolysis 50 years after the discovery of lysosome.Display Omitted► We discuss the emerging role of the caspase-8 in cellular survival and activation. ► Caspase-8 homodimer is pro-apoptotic; the heterodimer with FLIPL is pro-survival. ► Control of RIPK1 activity is an essential function of caspase-8. ► Heterodimer in complex with FADD and RIPK1 activates NF-κB, only if FLIPL is cleaved. ► Further cleavage of the caspase-8 inter-subunit linker turns the heterodimer pro-apoptotic.
Keywords: Abbreviations; ALPS; acute lympho-proliferative syndrome; CARD; caspase recruitment domain; CED; Caenorhabditis elegans; death protein; DD; death domain; DED; death effector domain; DISC; death inducing signaling complex; DR; death receptor; FADD; Fas-associated death domain protein; FLIP; FLICE inhibitory protein; HDAC; histone deacetylase; ICE; interleukin converting enzyme; IL; interleukin; IRF; interferon regulatory factor; JNK; c-Jun N-terminal kinase; NEMO; NF-κB essential modulator; NF; nuclear factor; RIPK; receptor interacting protein kinase; ROS; reactive oxygen species; TNF; tumor necrosis factor; TNFR; TNF receptor; TRADD; TNFR associated death domain protein; TRAF; TNFR associated factor; TWEAK; TNF-related weak inducer of apoptosisApoptosis; Caspase; FLIP; Necroptosis; Receptor interacting protein kinase
Proliferative versus apoptotic functions of caspase-8 by Bram J. van Raam; Guy S. Salvesen (pp. 113-122).
Caspase-8, the initiator of extrinsically-triggered apoptosis, also has important functions in cellular activation and differentiation downstream of a variety of cell surface receptors. It has become increasingly clear that the heterodimer of caspase-8 with the long isoform of cellular FLIP (FLIPL) fulfills these pro-survival functions of caspase-8. FLIPL, a catalytically defective caspase-8 paralog, can interact with caspase-8 to activate its catalytic function. The caspase-8/FLIPL heterodimer has a restricted substrate repertoire and does not induce apoptosis. In essence, caspase-8 heterodimerized with FLIPL prevents the receptor interacting kinases RIPK1 and -3 from executing the form of cell death known as necroptosis. This review discusses the latest insights in caspase-8 homo- versus heterodimerization and the implication this has for cellular death or survival. This article is part of a Special Issue entitled: Proteolysis 50 years after the discovery of lysosome.Display Omitted► We discuss the emerging role of the caspase-8 in cellular survival and activation. ► Caspase-8 homodimer is pro-apoptotic; the heterodimer with FLIPL is pro-survival. ► Control of RIPK1 activity is an essential function of caspase-8. ► Heterodimer in complex with FADD and RIPK1 activates NF-κB, only if FLIPL is cleaved. ► Further cleavage of the caspase-8 inter-subunit linker turns the heterodimer pro-apoptotic.
Keywords: Abbreviations; ALPS; acute lympho-proliferative syndrome; CARD; caspase recruitment domain; CED; Caenorhabditis elegans; death protein; DD; death domain; DED; death effector domain; DISC; death inducing signaling complex; DR; death receptor; FADD; Fas-associated death domain protein; FLIP; FLICE inhibitory protein; HDAC; histone deacetylase; ICE; interleukin converting enzyme; IL; interleukin; IRF; interferon regulatory factor; JNK; c-Jun N-terminal kinase; NEMO; NF-κB essential modulator; NF; nuclear factor; RIPK; receptor interacting protein kinase; ROS; reactive oxygen species; TNF; tumor necrosis factor; TNFR; TNF receptor; TRADD; TNFR associated death domain protein; TRAF; TNFR associated factor; TWEAK; TNF-related weak inducer of apoptosisApoptosis; Caspase; FLIP; Necroptosis; Receptor interacting protein kinase
Live-cell imaging of tumor proteolysis: Impact of cellular and non-cellular microenvironment by Jennifer M. Rothberg; Mansoureh Sameni; Kamiar Moin; Bonnie F. Sloane (pp. 123-132).
Our laboratory has had a longstanding interest in how the interactions between tumors and their microenvironment affect malignant progression. Recently, we have focused on defining the proteolytic pathways that function in the transition of breast cancer from the pre-invasive lesions of ductal carcinoma in situ (DCIS) to invasive ductal carcinomas (IDCs). We use live-cell imaging to visualize, localize and quantify proteolysis as it occurs in real-time and thereby have established roles for lysosomal cysteine proteases both pericellularly and intracellularly in tumor proteolysis. To facilitate these studies, we have developed and optimized 3D organotypic co-culture models that recapitulate the in vivo interactions of mammary epithelial cells or tumor cells with stromal and inflammatory cells. Here we will discuss the background that led to our present studies as well as the techniques and models that we employ. This article is part of a Special Issue entitled: Proteolysis 50 years after the discovery of lysosome.► Lysosomal proteases contribute to intracellular and pericellular tumor proteolysis. ► Pericellular tumor proteolysis occurs at focal sites on the cell surface. ► Pericellular proteolysis is increased by an acidic tumor microenvironment. ► Tumor and tumor-associated cells mediate proteolysis in the microenvironment. ► Tumor proteolysis can be localized in real-time by live-cell imaging techniques.
Keywords: Abbreviations; 3D/4D; three/four dimensional; DCIS; ductal carcinoma; in situ; DQ; dye-quenched; FAP; fibroblast activation protein; GPI; glycosylphosphatidylinositol; IDC; invasive ductal carcinoma; MAME; mammary architecture and microenvironment engineering; MMP; matrix metalloproteinase; MMPIs; matrix metalloproteinase inhibitors; MT-MMP; membrane type-MMP; PAI-1; plasminogen activator inhibitor-1; pHe; extracellular pH; rBM; reconstituted basement membrane; TIMP; tissue inhibitors of metalloproteinases; TTSPs; type II transmembrane serine proteases; uPA; urokinase plasminogen activator; uPAR; urokinase plasminogen activator receptor; uPARAP; urokinase plasminogen activator receptor associated proteinLysosomal proteases; Proteolytic networks; Functional imaging; 3D culture; Organotypic models; Tumor microenvironment
Live-cell imaging of tumor proteolysis: Impact of cellular and non-cellular microenvironment by Jennifer M. Rothberg; Mansoureh Sameni; Kamiar Moin; Bonnie F. Sloane (pp. 123-132).
Our laboratory has had a longstanding interest in how the interactions between tumors and their microenvironment affect malignant progression. Recently, we have focused on defining the proteolytic pathways that function in the transition of breast cancer from the pre-invasive lesions of ductal carcinoma in situ (DCIS) to invasive ductal carcinomas (IDCs). We use live-cell imaging to visualize, localize and quantify proteolysis as it occurs in real-time and thereby have established roles for lysosomal cysteine proteases both pericellularly and intracellularly in tumor proteolysis. To facilitate these studies, we have developed and optimized 3D organotypic co-culture models that recapitulate the in vivo interactions of mammary epithelial cells or tumor cells with stromal and inflammatory cells. Here we will discuss the background that led to our present studies as well as the techniques and models that we employ. This article is part of a Special Issue entitled: Proteolysis 50 years after the discovery of lysosome.► Lysosomal proteases contribute to intracellular and pericellular tumor proteolysis. ► Pericellular tumor proteolysis occurs at focal sites on the cell surface. ► Pericellular proteolysis is increased by an acidic tumor microenvironment. ► Tumor and tumor-associated cells mediate proteolysis in the microenvironment. ► Tumor proteolysis can be localized in real-time by live-cell imaging techniques.
Keywords: Abbreviations; 3D/4D; three/four dimensional; DCIS; ductal carcinoma; in situ; DQ; dye-quenched; FAP; fibroblast activation protein; GPI; glycosylphosphatidylinositol; IDC; invasive ductal carcinoma; MAME; mammary architecture and microenvironment engineering; MMP; matrix metalloproteinase; MMPIs; matrix metalloproteinase inhibitors; MT-MMP; membrane type-MMP; PAI-1; plasminogen activator inhibitor-1; pHe; extracellular pH; rBM; reconstituted basement membrane; TIMP; tissue inhibitors of metalloproteinases; TTSPs; type II transmembrane serine proteases; uPA; urokinase plasminogen activator; uPAR; urokinase plasminogen activator receptor; uPARAP; urokinase plasminogen activator receptor associated proteinLysosomal proteases; Proteolytic networks; Functional imaging; 3D culture; Organotypic models; Tumor microenvironment
Live-cell imaging of tumor proteolysis: Impact of cellular and non-cellular microenvironment by Jennifer M. Rothberg; Mansoureh Sameni; Kamiar Moin; Bonnie F. Sloane (pp. 123-132).
Our laboratory has had a longstanding interest in how the interactions between tumors and their microenvironment affect malignant progression. Recently, we have focused on defining the proteolytic pathways that function in the transition of breast cancer from the pre-invasive lesions of ductal carcinoma in situ (DCIS) to invasive ductal carcinomas (IDCs). We use live-cell imaging to visualize, localize and quantify proteolysis as it occurs in real-time and thereby have established roles for lysosomal cysteine proteases both pericellularly and intracellularly in tumor proteolysis. To facilitate these studies, we have developed and optimized 3D organotypic co-culture models that recapitulate the in vivo interactions of mammary epithelial cells or tumor cells with stromal and inflammatory cells. Here we will discuss the background that led to our present studies as well as the techniques and models that we employ. This article is part of a Special Issue entitled: Proteolysis 50 years after the discovery of lysosome.► Lysosomal proteases contribute to intracellular and pericellular tumor proteolysis. ► Pericellular tumor proteolysis occurs at focal sites on the cell surface. ► Pericellular proteolysis is increased by an acidic tumor microenvironment. ► Tumor and tumor-associated cells mediate proteolysis in the microenvironment. ► Tumor proteolysis can be localized in real-time by live-cell imaging techniques.
Keywords: Abbreviations; 3D/4D; three/four dimensional; DCIS; ductal carcinoma; in situ; DQ; dye-quenched; FAP; fibroblast activation protein; GPI; glycosylphosphatidylinositol; IDC; invasive ductal carcinoma; MAME; mammary architecture and microenvironment engineering; MMP; matrix metalloproteinase; MMPIs; matrix metalloproteinase inhibitors; MT-MMP; membrane type-MMP; PAI-1; plasminogen activator inhibitor-1; pHe; extracellular pH; rBM; reconstituted basement membrane; TIMP; tissue inhibitors of metalloproteinases; TTSPs; type II transmembrane serine proteases; uPA; urokinase plasminogen activator; uPAR; urokinase plasminogen activator receptor; uPARAP; urokinase plasminogen activator receptor associated proteinLysosomal proteases; Proteolytic networks; Functional imaging; 3D culture; Organotypic models; Tumor microenvironment
Proteases involved in cartilage matrix degradation in osteoarthritis by Linda Troeberg; Hideaki Nagase (pp. 133-145).
Osteoarthritis is a common joint disease for which there are currently no disease-modifying drugs available. Degradation of the cartilage extracellular matrix is a central feature of the disease and is widely thought to be mediated by proteinases that degrade structural components of the matrix, primarily aggrecan and collagen. Studies on transgenic mice have confirmed the central role of Adamalysin with Thrombospondin Motifs 5 (ADAMTS-5) in aggrecan degradation, and the collagenolytic matrix metalloproteinase MMP-13 in collagen degradation. This review discusses recent advances in current understanding of the mechanisms regulating expression of these key enzymes, as well as reviewing the roles of other proteinases in cartilage destruction. This article is part of a Special Issue entitled: Proteolysis 50years after the discovery of lysosome.► Osteoarthritis is characterised by degradation of cartilage extracellular matrix. ► Collagen is degraded by matrix metalloproteinases such as MMP-13. ► Aggrecan is degraded by related ADAMTS metalloproteinases. ► Less abundant cartilage components are degraded by a variety of proteinases. ► Factors such as inflammation and mechanical damage stimulate enzyme expression.
Keywords: Abbreviations; ADAMTS; a disintegrin and metalloproteinase with thrombospondin motifs; APC; activated protein C; CITED2; cAMP-responsive element-binding protein/p300-interacting transactivator with Glu/Asp-rich carboxy-terminal domain 2; ECM; extracellular matrix; ERK; extracellularly-regulated kinase; FAPα; fibroblast activation protein α; FGF-2; fibroblast growth factor 2; Gla; γ-carboxyglutamate; HDAC; histone deacetylase; HIF-2α; hypoxia-inducible factor 2α; IGD; interglobular domain; IGF; insulin-like growth factor; IGFBP; IGF binding protein; MMP; matrix metalloproteinase; OA; osteoarthritis; PACE4; paired basic amino acid cleaving enzyme 4; PAR; protease-activated receptor; PC; proprotein convertase; RUNX2; runt-related transcription factor 2; SIRT1; Sirtuin 1; TIMP; tissue inhibitor of metalloproteinases; tPA; tissue-type plasminogen activator; uPA; urokinase-type plasminogen activator; WISP-1; Wnt-induced signalling protein 1Osteoarthritis; Proteinase; Cartilage; Aggrecanase; Collagenase
Proteases involved in cartilage matrix degradation in osteoarthritis by Linda Troeberg; Hideaki Nagase (pp. 133-145).
Osteoarthritis is a common joint disease for which there are currently no disease-modifying drugs available. Degradation of the cartilage extracellular matrix is a central feature of the disease and is widely thought to be mediated by proteinases that degrade structural components of the matrix, primarily aggrecan and collagen. Studies on transgenic mice have confirmed the central role of Adamalysin with Thrombospondin Motifs 5 (ADAMTS-5) in aggrecan degradation, and the collagenolytic matrix metalloproteinase MMP-13 in collagen degradation. This review discusses recent advances in current understanding of the mechanisms regulating expression of these key enzymes, as well as reviewing the roles of other proteinases in cartilage destruction. This article is part of a Special Issue entitled: Proteolysis 50years after the discovery of lysosome.► Osteoarthritis is characterised by degradation of cartilage extracellular matrix. ► Collagen is degraded by matrix metalloproteinases such as MMP-13. ► Aggrecan is degraded by related ADAMTS metalloproteinases. ► Less abundant cartilage components are degraded by a variety of proteinases. ► Factors such as inflammation and mechanical damage stimulate enzyme expression.
Keywords: Abbreviations; ADAMTS; a disintegrin and metalloproteinase with thrombospondin motifs; APC; activated protein C; CITED2; cAMP-responsive element-binding protein/p300-interacting transactivator with Glu/Asp-rich carboxy-terminal domain 2; ECM; extracellular matrix; ERK; extracellularly-regulated kinase; FAPα; fibroblast activation protein α; FGF-2; fibroblast growth factor 2; Gla; γ-carboxyglutamate; HDAC; histone deacetylase; HIF-2α; hypoxia-inducible factor 2α; IGD; interglobular domain; IGF; insulin-like growth factor; IGFBP; IGF binding protein; MMP; matrix metalloproteinase; OA; osteoarthritis; PACE4; paired basic amino acid cleaving enzyme 4; PAR; protease-activated receptor; PC; proprotein convertase; RUNX2; runt-related transcription factor 2; SIRT1; Sirtuin 1; TIMP; tissue inhibitor of metalloproteinases; tPA; tissue-type plasminogen activator; uPA; urokinase-type plasminogen activator; WISP-1; Wnt-induced signalling protein 1Osteoarthritis; Proteinase; Cartilage; Aggrecanase; Collagenase
Proteases involved in cartilage matrix degradation in osteoarthritis by Linda Troeberg; Hideaki Nagase (pp. 133-145).
Osteoarthritis is a common joint disease for which there are currently no disease-modifying drugs available. Degradation of the cartilage extracellular matrix is a central feature of the disease and is widely thought to be mediated by proteinases that degrade structural components of the matrix, primarily aggrecan and collagen. Studies on transgenic mice have confirmed the central role of Adamalysin with Thrombospondin Motifs 5 (ADAMTS-5) in aggrecan degradation, and the collagenolytic matrix metalloproteinase MMP-13 in collagen degradation. This review discusses recent advances in current understanding of the mechanisms regulating expression of these key enzymes, as well as reviewing the roles of other proteinases in cartilage destruction. This article is part of a Special Issue entitled: Proteolysis 50years after the discovery of lysosome.► Osteoarthritis is characterised by degradation of cartilage extracellular matrix. ► Collagen is degraded by matrix metalloproteinases such as MMP-13. ► Aggrecan is degraded by related ADAMTS metalloproteinases. ► Less abundant cartilage components are degraded by a variety of proteinases. ► Factors such as inflammation and mechanical damage stimulate enzyme expression.
Keywords: Abbreviations; ADAMTS; a disintegrin and metalloproteinase with thrombospondin motifs; APC; activated protein C; CITED2; cAMP-responsive element-binding protein/p300-interacting transactivator with Glu/Asp-rich carboxy-terminal domain 2; ECM; extracellular matrix; ERK; extracellularly-regulated kinase; FAPα; fibroblast activation protein α; FGF-2; fibroblast growth factor 2; Gla; γ-carboxyglutamate; HDAC; histone deacetylase; HIF-2α; hypoxia-inducible factor 2α; IGD; interglobular domain; IGF; insulin-like growth factor; IGFBP; IGF binding protein; MMP; matrix metalloproteinase; OA; osteoarthritis; PACE4; paired basic amino acid cleaving enzyme 4; PAR; protease-activated receptor; PC; proprotein convertase; RUNX2; runt-related transcription factor 2; SIRT1; Sirtuin 1; TIMP; tissue inhibitor of metalloproteinases; tPA; tissue-type plasminogen activator; uPA; urokinase-type plasminogen activator; WISP-1; Wnt-induced signalling protein 1Osteoarthritis; Proteinase; Cartilage; Aggrecanase; Collagenase
Regulation of matrix metalloproteinases activity studied in human endometrium as a paradigm of cyclic tissue breakdown and regeneration by Héloïse P. Gaide Chevronnay; Charlotte Selvais; Hervé Emonard; Christine Galant; Etienne Marbaix; Patrick Henriet (pp. 146-156).
When abundant and activated, matrix metalloproteinases (MMPs, or matrixins) degrade most, if not all, constituents of the extracellular matrix (ECM). The resulting massive tissue breakdown is best exemplified in humans by the menstrual lysis and shedding of the endometrium, the mucosa lining the uterus. After menstruation, MMP activity needs to be tightly controlled as the endometrium regenerates and differentiates to avoid abnormal tissue breakdown while allowing tissue repair and fine remodelling to accommodate implantation of a blastocyst. This paper reviews how MMPs are massively present and activated in the endometrium at menstruation, and how their activity is tightly controlled at other phases of the cycle. Progesterone represses expression of many but not all MMPs. Its withdrawal triggers focal expression of MMPs specifically in the areas undergoing lysis, an effect mediated by local cytokines such as interleukin-1α, LEFTY-2, tumour necrosis factor-α and others. MMP-3 is selectively expressed at that time and activates proMMP-9, otherwise present in latent form throughout the cycle. In addition, a large number of neutrophils loaded with MMPs are recruited at menstruation through induction of chemokines, such as interleukin-8. At the secretory phase, progesterone repression of MMPs is mediated by transforming growth factor-β. Tissue inhibitors of metalloproteinases (TIMPs) are abundant at all phases of the cycle to prevent any undue MMP activity, but are likely overwhelmed at menstruation. At other phases of the cycle, MMPs can elude TIMP inhibition as exemplified by recruitment of active MMP-7 to the plasma membrane of epithelial cells, allowing processing of membrane-associated growth factors needed for epithelial repair and proliferation. Finally, receptor-mediated endocytosis through low density lipoprotein receptor-related protein-1 (LRP-1) efficiently clears MMP-2 and -9 at the proliferative and secretory phases. This mechanism is probably essential to prevent any excessive ECM degradation by the active form of MMP-2 that is permanently present. However, shedding of the ectodomain of LRP-1 specifically at menstruation prevents endocytosis of MMPs allowing full degradation of the ECM. Thus endometrial MMPs are regulated at the levels of transcription, release from infiltrating neutrophils, activation, binding to the cell membrane, inhibition by TIMPs and endocytic clearance by LRP-1. This allows tight control during endometrial growth and differentiation but results in a burst of activity for menstrual tissue breakdown. This article is part of a Special Issue entitled: Proteolysis 50 years after the discovery of lysosome.► Human endometrium is lysed by matrix metalloproteinases (MMPs) at each menstruation. ► MMP activity needs to be tightly controlled at other phases of the menstrual cycle. ► Progesterone regulates MMP expression, activation, inhibition and endocytosis. ► MMPs recruited at cell membrane are locally active despite TIMPs.
Keywords: Abbreviations; ADAM; a disintegrin and metalloproteinase; ECM; extracellular matrix; EGF; epidermal growth factor; GPI; glycosylphosphatidylinositol; HSPG; heparan sulfate proteoglycan; IGF; insulin-like growth factor; IL; interleukin; LRP; low density lipoprotein receptor-related protein; MMP; matrix metalloproteinase; MT; membrane-type; NGAL; neutrophil gelatinase-associated lipocalin-like; NK; natural killer; PA; plasminogen activator; PAI; plasminogen activator inhibitor; PDGF; platelet-derived growth factor; TGF; transforming growth factor; TIMP; tissue inhibitor of metalloproteinases; TNF; tumour necrosis factor; uPA; urokinaseMatrix metalloproteinase; Collagenase; Gelatinase; Endometrium; Menstruation; Extracellular matrix
Regulation of matrix metalloproteinases activity studied in human endometrium as a paradigm of cyclic tissue breakdown and regeneration by Héloïse P. Gaide Chevronnay; Charlotte Selvais; Hervé Emonard; Christine Galant; Etienne Marbaix; Patrick Henriet (pp. 146-156).
When abundant and activated, matrix metalloproteinases (MMPs, or matrixins) degrade most, if not all, constituents of the extracellular matrix (ECM). The resulting massive tissue breakdown is best exemplified in humans by the menstrual lysis and shedding of the endometrium, the mucosa lining the uterus. After menstruation, MMP activity needs to be tightly controlled as the endometrium regenerates and differentiates to avoid abnormal tissue breakdown while allowing tissue repair and fine remodelling to accommodate implantation of a blastocyst. This paper reviews how MMPs are massively present and activated in the endometrium at menstruation, and how their activity is tightly controlled at other phases of the cycle. Progesterone represses expression of many but not all MMPs. Its withdrawal triggers focal expression of MMPs specifically in the areas undergoing lysis, an effect mediated by local cytokines such as interleukin-1α, LEFTY-2, tumour necrosis factor-α and others. MMP-3 is selectively expressed at that time and activates proMMP-9, otherwise present in latent form throughout the cycle. In addition, a large number of neutrophils loaded with MMPs are recruited at menstruation through induction of chemokines, such as interleukin-8. At the secretory phase, progesterone repression of MMPs is mediated by transforming growth factor-β. Tissue inhibitors of metalloproteinases (TIMPs) are abundant at all phases of the cycle to prevent any undue MMP activity, but are likely overwhelmed at menstruation. At other phases of the cycle, MMPs can elude TIMP inhibition as exemplified by recruitment of active MMP-7 to the plasma membrane of epithelial cells, allowing processing of membrane-associated growth factors needed for epithelial repair and proliferation. Finally, receptor-mediated endocytosis through low density lipoprotein receptor-related protein-1 (LRP-1) efficiently clears MMP-2 and -9 at the proliferative and secretory phases. This mechanism is probably essential to prevent any excessive ECM degradation by the active form of MMP-2 that is permanently present. However, shedding of the ectodomain of LRP-1 specifically at menstruation prevents endocytosis of MMPs allowing full degradation of the ECM. Thus endometrial MMPs are regulated at the levels of transcription, release from infiltrating neutrophils, activation, binding to the cell membrane, inhibition by TIMPs and endocytic clearance by LRP-1. This allows tight control during endometrial growth and differentiation but results in a burst of activity for menstrual tissue breakdown. This article is part of a Special Issue entitled: Proteolysis 50 years after the discovery of lysosome.► Human endometrium is lysed by matrix metalloproteinases (MMPs) at each menstruation. ► MMP activity needs to be tightly controlled at other phases of the menstrual cycle. ► Progesterone regulates MMP expression, activation, inhibition and endocytosis. ► MMPs recruited at cell membrane are locally active despite TIMPs.
Keywords: Abbreviations; ADAM; a disintegrin and metalloproteinase; ECM; extracellular matrix; EGF; epidermal growth factor; GPI; glycosylphosphatidylinositol; HSPG; heparan sulfate proteoglycan; IGF; insulin-like growth factor; IL; interleukin; LRP; low density lipoprotein receptor-related protein; MMP; matrix metalloproteinase; MT; membrane-type; NGAL; neutrophil gelatinase-associated lipocalin-like; NK; natural killer; PA; plasminogen activator; PAI; plasminogen activator inhibitor; PDGF; platelet-derived growth factor; TGF; transforming growth factor; TIMP; tissue inhibitor of metalloproteinases; TNF; tumour necrosis factor; uPA; urokinaseMatrix metalloproteinase; Collagenase; Gelatinase; Endometrium; Menstruation; Extracellular matrix
Regulation of matrix metalloproteinases activity studied in human endometrium as a paradigm of cyclic tissue breakdown and regeneration by Héloïse P. Gaide Chevronnay; Charlotte Selvais; Hervé Emonard; Christine Galant; Etienne Marbaix; Patrick Henriet (pp. 146-156).
When abundant and activated, matrix metalloproteinases (MMPs, or matrixins) degrade most, if not all, constituents of the extracellular matrix (ECM). The resulting massive tissue breakdown is best exemplified in humans by the menstrual lysis and shedding of the endometrium, the mucosa lining the uterus. After menstruation, MMP activity needs to be tightly controlled as the endometrium regenerates and differentiates to avoid abnormal tissue breakdown while allowing tissue repair and fine remodelling to accommodate implantation of a blastocyst. This paper reviews how MMPs are massively present and activated in the endometrium at menstruation, and how their activity is tightly controlled at other phases of the cycle. Progesterone represses expression of many but not all MMPs. Its withdrawal triggers focal expression of MMPs specifically in the areas undergoing lysis, an effect mediated by local cytokines such as interleukin-1α, LEFTY-2, tumour necrosis factor-α and others. MMP-3 is selectively expressed at that time and activates proMMP-9, otherwise present in latent form throughout the cycle. In addition, a large number of neutrophils loaded with MMPs are recruited at menstruation through induction of chemokines, such as interleukin-8. At the secretory phase, progesterone repression of MMPs is mediated by transforming growth factor-β. Tissue inhibitors of metalloproteinases (TIMPs) are abundant at all phases of the cycle to prevent any undue MMP activity, but are likely overwhelmed at menstruation. At other phases of the cycle, MMPs can elude TIMP inhibition as exemplified by recruitment of active MMP-7 to the plasma membrane of epithelial cells, allowing processing of membrane-associated growth factors needed for epithelial repair and proliferation. Finally, receptor-mediated endocytosis through low density lipoprotein receptor-related protein-1 (LRP-1) efficiently clears MMP-2 and -9 at the proliferative and secretory phases. This mechanism is probably essential to prevent any excessive ECM degradation by the active form of MMP-2 that is permanently present. However, shedding of the ectodomain of LRP-1 specifically at menstruation prevents endocytosis of MMPs allowing full degradation of the ECM. Thus endometrial MMPs are regulated at the levels of transcription, release from infiltrating neutrophils, activation, binding to the cell membrane, inhibition by TIMPs and endocytic clearance by LRP-1. This allows tight control during endometrial growth and differentiation but results in a burst of activity for menstrual tissue breakdown. This article is part of a Special Issue entitled: Proteolysis 50 years after the discovery of lysosome.► Human endometrium is lysed by matrix metalloproteinases (MMPs) at each menstruation. ► MMP activity needs to be tightly controlled at other phases of the menstrual cycle. ► Progesterone regulates MMP expression, activation, inhibition and endocytosis. ► MMPs recruited at cell membrane are locally active despite TIMPs.
Keywords: Abbreviations; ADAM; a disintegrin and metalloproteinase; ECM; extracellular matrix; EGF; epidermal growth factor; GPI; glycosylphosphatidylinositol; HSPG; heparan sulfate proteoglycan; IGF; insulin-like growth factor; IL; interleukin; LRP; low density lipoprotein receptor-related protein; MMP; matrix metalloproteinase; MT; membrane-type; NGAL; neutrophil gelatinase-associated lipocalin-like; NK; natural killer; PA; plasminogen activator; PAI; plasminogen activator inhibitor; PDGF; platelet-derived growth factor; TGF; transforming growth factor; TIMP; tissue inhibitor of metalloproteinases; TNF; tumour necrosis factor; uPA; urokinaseMatrix metalloproteinase; Collagenase; Gelatinase; Endometrium; Menstruation; Extracellular matrix
A standard orientation for metallopeptidases by Gomis-Ruth F. Xavier Gomis-Rüth; Tiago O. Botelho; Wolfram Bode (pp. 157-163).
Visualization of three-dimensional structures is essential to the transmission of information to the general reader and the comparison of related structures. Therefore, it would be useful to provide a common framework. Based on the work of Schechter and Berger, and the finding that most peptidases bind their substrates in extended conformation, we suggest a “standard orientation” for the overall description of metallopeptidases (MPs) as done before for peptidases of other classes. This entails a frontal view of the horizontally-aligned active-site cleft. A substrate is bound N- to C-terminally from left (on the non-primed side of the cleft) to right (on the primed side), and the catalytic metal ion resides at the cleft bottom at roughly half width. This view enables us to see that most metalloendopeptidases are bifurcated into an upper and a lower sub-domain by the cleft, whose back is framed by a nearly horizontal “active-site helix.” The latter comprises a short zinc-binding consensus sequence, either HEXXH or HXXEH, which provides two histidines to bind the single catalytic metal and the general-base/acid glutamate required for catalysis. In addition, an oblique “backing helix” is observed behind the active-site helix, and a mixed β-sheet of at least three strands is positioned in the upper sub-domain paralleling the cleft. The lowermost “upper-rim” strand of the sheet runs antiparallel to the substrate bound in the cleft and therefore contributes both to delimitating the cleft top and to binding of the substrate main-chain on its non-primed side through β-ribbon-like interactions. In contrast, in metalloexopeptidases, which chop off N- or C-terminal residues only, extensive binding on both sides of the cleft is not required and a different overall scaffold is generally observed. This consists of an αβα-sandwich, which is reminiscent of, but clearly distinct from, the archetypal α/β-hydrolase fold. Metalloexopeptidases have their active sites at the C-terminal end of a central, eight-stranded twisted β-sheet, and can contain one or two catalytic metal ions. As the zinc-binding site and the residues engaged in substrate binding and catalysis are mainly provided by loops connecting the β-sheet strands and the helices on either side, the respective standard orientations vary with respect to the position of the sheets. The standard orientation of eight prototypic MP structures is presented and discussed. This article is part of a Special Issue entitled: Proteolysis 50 years after the discovery of lysosome.
Keywords: Metallopeptidases; Active-site cleft; Visualization; Catalytic mechanism; Three-dimensional structure; Catalytic metal ion
A standard orientation for metallopeptidases by Gomis-Ruth F. Xavier Gomis-Rüth; Tiago O. Botelho; Wolfram Bode (pp. 157-163).
Visualization of three-dimensional structures is essential to the transmission of information to the general reader and the comparison of related structures. Therefore, it would be useful to provide a common framework. Based on the work of Schechter and Berger, and the finding that most peptidases bind their substrates in extended conformation, we suggest a “standard orientation” for the overall description of metallopeptidases (MPs) as done before for peptidases of other classes. This entails a frontal view of the horizontally-aligned active-site cleft. A substrate is bound N- to C-terminally from left (on the non-primed side of the cleft) to right (on the primed side), and the catalytic metal ion resides at the cleft bottom at roughly half width. This view enables us to see that most metalloendopeptidases are bifurcated into an upper and a lower sub-domain by the cleft, whose back is framed by a nearly horizontal “active-site helix.” The latter comprises a short zinc-binding consensus sequence, either HEXXH or HXXEH, which provides two histidines to bind the single catalytic metal and the general-base/acid glutamate required for catalysis. In addition, an oblique “backing helix” is observed behind the active-site helix, and a mixed β-sheet of at least three strands is positioned in the upper sub-domain paralleling the cleft. The lowermost “upper-rim” strand of the sheet runs antiparallel to the substrate bound in the cleft and therefore contributes both to delimitating the cleft top and to binding of the substrate main-chain on its non-primed side through β-ribbon-like interactions. In contrast, in metalloexopeptidases, which chop off N- or C-terminal residues only, extensive binding on both sides of the cleft is not required and a different overall scaffold is generally observed. This consists of an αβα-sandwich, which is reminiscent of, but clearly distinct from, the archetypal α/β-hydrolase fold. Metalloexopeptidases have their active sites at the C-terminal end of a central, eight-stranded twisted β-sheet, and can contain one or two catalytic metal ions. As the zinc-binding site and the residues engaged in substrate binding and catalysis are mainly provided by loops connecting the β-sheet strands and the helices on either side, the respective standard orientations vary with respect to the position of the sheets. The standard orientation of eight prototypic MP structures is presented and discussed. This article is part of a Special Issue entitled: Proteolysis 50 years after the discovery of lysosome.
Keywords: Metallopeptidases; Active-site cleft; Visualization; Catalytic mechanism; Three-dimensional structure; Catalytic metal ion
A standard orientation for metallopeptidases by Gomis-Ruth F. Xavier Gomis-Rüth; Tiago O. Botelho; Wolfram Bode (pp. 157-163).
Visualization of three-dimensional structures is essential to the transmission of information to the general reader and the comparison of related structures. Therefore, it would be useful to provide a common framework. Based on the work of Schechter and Berger, and the finding that most peptidases bind their substrates in extended conformation, we suggest a “standard orientation” for the overall description of metallopeptidases (MPs) as done before for peptidases of other classes. This entails a frontal view of the horizontally-aligned active-site cleft. A substrate is bound N- to C-terminally from left (on the non-primed side of the cleft) to right (on the primed side), and the catalytic metal ion resides at the cleft bottom at roughly half width. This view enables us to see that most metalloendopeptidases are bifurcated into an upper and a lower sub-domain by the cleft, whose back is framed by a nearly horizontal “active-site helix.” The latter comprises a short zinc-binding consensus sequence, either HEXXH or HXXEH, which provides two histidines to bind the single catalytic metal and the general-base/acid glutamate required for catalysis. In addition, an oblique “backing helix” is observed behind the active-site helix, and a mixed β-sheet of at least three strands is positioned in the upper sub-domain paralleling the cleft. The lowermost “upper-rim” strand of the sheet runs antiparallel to the substrate bound in the cleft and therefore contributes both to delimitating the cleft top and to binding of the substrate main-chain on its non-primed side through β-ribbon-like interactions. In contrast, in metalloexopeptidases, which chop off N- or C-terminal residues only, extensive binding on both sides of the cleft is not required and a different overall scaffold is generally observed. This consists of an αβα-sandwich, which is reminiscent of, but clearly distinct from, the archetypal α/β-hydrolase fold. Metalloexopeptidases have their active sites at the C-terminal end of a central, eight-stranded twisted β-sheet, and can contain one or two catalytic metal ions. As the zinc-binding site and the residues engaged in substrate binding and catalysis are mainly provided by loops connecting the β-sheet strands and the helices on either side, the respective standard orientations vary with respect to the position of the sheets. The standard orientation of eight prototypic MP structures is presented and discussed. This article is part of a Special Issue entitled: Proteolysis 50 years after the discovery of lysosome.
Keywords: Metallopeptidases; Active-site cleft; Visualization; Catalytic mechanism; Three-dimensional structure; Catalytic metal ion
Snake venom metalloproteinases: Structure, function and relevance to the mammalian ADAM/ADAMTS family proteins by Soichi Takeda; Hiroyuki Takeya; Sadaaki Iwanaga (pp. 164-176).
Metalloproteinases are among the most abundant toxins in many Viperidae venoms. Snake venom metalloproteinases (SVMPs) are the primary factors responsible for hemorrhage and may also interfere with the hemostatic system, thus facilitating loss of blood from the vasculature of the prey. SVMPs are phylogenetically most closely related to mammalian ADAM (a disintegrinandmetalloproteinase) and ADAMTS (ADAM withthrombospondin type-1 motif) family of proteins and, together with them, constitute the M12B clan of metalloendopeptidases. Large SVMPs, referred to as the P-III class of SVMPs, have a modular architecture with multiple non-catalytic domains. The P-III SVMPs are characterized by higher hemorrhagic and more diverse biological activities than the P-I class of SVMPs, which only have a catalytic domain. Recent crystallographic studies of P-III SVMPs and their mammalian counterparts shed new light on structure–function properties of this class of enzymes. The present review will highlight these structures, particularly the non-catalytic ancillary domains of P-III SVMPs and ADAMs that may target the enzymes to specific substrates. This article is part of a Special Issue entitled: Proteolysis 50years after the discovery of lysosome.► Snake venom metalloproteinases (SVMPs) are highly abundant in many viper venoms. ► SVMPs can cause hemorrhage and disruption of hemostasis upon envenomation. ► SVMPs and mammalian ADAM/ADAMTS proteins constitute the M12B clan of endopeptidases. ► Large SVMPs and ADAMs/ADAMTSs have multiple non-catalytic domains. ► These ancillary domains may target the enzyme to specific substrates.
Keywords: Snake venom metalloproteinase; Disintegrin; MDC protein; ADAM; ADAMTS
Snake venom metalloproteinases: Structure, function and relevance to the mammalian ADAM/ADAMTS family proteins by Soichi Takeda; Hiroyuki Takeya; Sadaaki Iwanaga (pp. 164-176).
Metalloproteinases are among the most abundant toxins in many Viperidae venoms. Snake venom metalloproteinases (SVMPs) are the primary factors responsible for hemorrhage and may also interfere with the hemostatic system, thus facilitating loss of blood from the vasculature of the prey. SVMPs are phylogenetically most closely related to mammalian ADAM (a disintegrinandmetalloproteinase) and ADAMTS (ADAM withthrombospondin type-1 motif) family of proteins and, together with them, constitute the M12B clan of metalloendopeptidases. Large SVMPs, referred to as the P-III class of SVMPs, have a modular architecture with multiple non-catalytic domains. The P-III SVMPs are characterized by higher hemorrhagic and more diverse biological activities than the P-I class of SVMPs, which only have a catalytic domain. Recent crystallographic studies of P-III SVMPs and their mammalian counterparts shed new light on structure–function properties of this class of enzymes. The present review will highlight these structures, particularly the non-catalytic ancillary domains of P-III SVMPs and ADAMs that may target the enzymes to specific substrates. This article is part of a Special Issue entitled: Proteolysis 50years after the discovery of lysosome.► Snake venom metalloproteinases (SVMPs) are highly abundant in many viper venoms. ► SVMPs can cause hemorrhage and disruption of hemostasis upon envenomation. ► SVMPs and mammalian ADAM/ADAMTS proteins constitute the M12B clan of endopeptidases. ► Large SVMPs and ADAMs/ADAMTSs have multiple non-catalytic domains. ► These ancillary domains may target the enzyme to specific substrates.
Keywords: Snake venom metalloproteinase; Disintegrin; MDC protein; ADAM; ADAMTS
Snake venom metalloproteinases: Structure, function and relevance to the mammalian ADAM/ADAMTS family proteins by Soichi Takeda; Hiroyuki Takeya; Sadaaki Iwanaga (pp. 164-176).
Metalloproteinases are among the most abundant toxins in many Viperidae venoms. Snake venom metalloproteinases (SVMPs) are the primary factors responsible for hemorrhage and may also interfere with the hemostatic system, thus facilitating loss of blood from the vasculature of the prey. SVMPs are phylogenetically most closely related to mammalian ADAM (a disintegrinandmetalloproteinase) and ADAMTS (ADAM withthrombospondin type-1 motif) family of proteins and, together with them, constitute the M12B clan of metalloendopeptidases. Large SVMPs, referred to as the P-III class of SVMPs, have a modular architecture with multiple non-catalytic domains. The P-III SVMPs are characterized by higher hemorrhagic and more diverse biological activities than the P-I class of SVMPs, which only have a catalytic domain. Recent crystallographic studies of P-III SVMPs and their mammalian counterparts shed new light on structure–function properties of this class of enzymes. The present review will highlight these structures, particularly the non-catalytic ancillary domains of P-III SVMPs and ADAMs that may target the enzymes to specific substrates. This article is part of a Special Issue entitled: Proteolysis 50years after the discovery of lysosome.► Snake venom metalloproteinases (SVMPs) are highly abundant in many viper venoms. ► SVMPs can cause hemorrhage and disruption of hemostasis upon envenomation. ► SVMPs and mammalian ADAM/ADAMTS proteins constitute the M12B clan of endopeptidases. ► Large SVMPs and ADAMs/ADAMTSs have multiple non-catalytic domains. ► These ancillary domains may target the enzyme to specific substrates.
Keywords: Snake venom metalloproteinase; Disintegrin; MDC protein; ADAM; ADAMTS
Proteases as regulators of pathogenesis: Examples from the Apicomplexa by Hao Li; Matthew A. Child; Matthew Bogyo (pp. 177-185).
The diverse functional roles that proteases play in basic biological processes make them essential for virtually all organisms. Not surprisingly, proteolysis is also a critical process required for many aspects of pathogenesis. In particular, obligate intracellular parasites must precisely coordinate proteolytic events during their highly regulated life cycle inside multiple host cell environments. Advances in chemical, proteomic and genetic tools that can be applied to parasite biology have led to an increased understanding of the complex events centrally regulated by proteases. In this review, we outline recent advances in our knowledge of specific proteolytic enzymes in two medically relevant apicomplexan parasites: Plasmodium falciparum and Toxoplasma gondii. Efforts over the last decade have begun to provide a map of key proteotolyic events that are essential for both parasite survival and propagation inside host cells. These advances in our molecular understanding of proteolytic events involved in parasite pathogenesis provide a foundation for the validation of new networks and enzyme targets that could be exploited for therapeutic purposes. This article is part of a Special Issue entitled: Proteolysis 50years after the discovery of lysosome.► Discussion of proteases as important mediators of pathogenesis in parasites. ► Outline of proteases in Plasmodium falciparum and Toxoplasma gondii. ► Discussion on pathogen proteases as potential novel anti-parasitic drug targets. ► Outline of advances that have increased understanding of parasite protease biology.
Keywords: Apicomplexans; Proteases; Pathogenesis; Plasmodium; Toxoplasma; Malaria
Proteases as regulators of pathogenesis: Examples from the Apicomplexa by Hao Li; Matthew A. Child; Matthew Bogyo (pp. 177-185).
The diverse functional roles that proteases play in basic biological processes make them essential for virtually all organisms. Not surprisingly, proteolysis is also a critical process required for many aspects of pathogenesis. In particular, obligate intracellular parasites must precisely coordinate proteolytic events during their highly regulated life cycle inside multiple host cell environments. Advances in chemical, proteomic and genetic tools that can be applied to parasite biology have led to an increased understanding of the complex events centrally regulated by proteases. In this review, we outline recent advances in our knowledge of specific proteolytic enzymes in two medically relevant apicomplexan parasites: Plasmodium falciparum and Toxoplasma gondii. Efforts over the last decade have begun to provide a map of key proteotolyic events that are essential for both parasite survival and propagation inside host cells. These advances in our molecular understanding of proteolytic events involved in parasite pathogenesis provide a foundation for the validation of new networks and enzyme targets that could be exploited for therapeutic purposes. This article is part of a Special Issue entitled: Proteolysis 50years after the discovery of lysosome.► Discussion of proteases as important mediators of pathogenesis in parasites. ► Outline of proteases in Plasmodium falciparum and Toxoplasma gondii. ► Discussion on pathogen proteases as potential novel anti-parasitic drug targets. ► Outline of advances that have increased understanding of parasite protease biology.
Keywords: Apicomplexans; Proteases; Pathogenesis; Plasmodium; Toxoplasma; Malaria
Proteases as regulators of pathogenesis: Examples from the Apicomplexa by Hao Li; Matthew A. Child; Matthew Bogyo (pp. 177-185).
The diverse functional roles that proteases play in basic biological processes make them essential for virtually all organisms. Not surprisingly, proteolysis is also a critical process required for many aspects of pathogenesis. In particular, obligate intracellular parasites must precisely coordinate proteolytic events during their highly regulated life cycle inside multiple host cell environments. Advances in chemical, proteomic and genetic tools that can be applied to parasite biology have led to an increased understanding of the complex events centrally regulated by proteases. In this review, we outline recent advances in our knowledge of specific proteolytic enzymes in two medically relevant apicomplexan parasites: Plasmodium falciparum and Toxoplasma gondii. Efforts over the last decade have begun to provide a map of key proteotolyic events that are essential for both parasite survival and propagation inside host cells. These advances in our molecular understanding of proteolytic events involved in parasite pathogenesis provide a foundation for the validation of new networks and enzyme targets that could be exploited for therapeutic purposes. This article is part of a Special Issue entitled: Proteolysis 50years after the discovery of lysosome.► Discussion of proteases as important mediators of pathogenesis in parasites. ► Outline of proteases in Plasmodium falciparum and Toxoplasma gondii. ► Discussion on pathogen proteases as potential novel anti-parasitic drug targets. ► Outline of advances that have increased understanding of parasite protease biology.
Keywords: Apicomplexans; Proteases; Pathogenesis; Plasmodium; Toxoplasma; Malaria
Role of host cellular proteases in the pathogenesis of influenza and influenza-induced multiple organ failure by Hiroshi Kido; Yuushi Okumura; Etsuhisa Takahashi; Hai-Yan Pan; Siye Wang; Dengbing Yao; Min Yao; Junji Chida; Mihiro Yano (pp. 186-194).
Influenza A virus (IAV) is one of the most common infectious pathogens in humans. Since the IVA genome does not have the processing protease for the viral hemagglutinin (HA) envelope glycoprotein precursors, entry of this virus into cells and infectious organ tropism of IAV are primarily determined by host cellular trypsin-type HA processing proteases. Several secretion-type HA processing proteases for seasonal IAV in the airway, and ubiquitously expressed furin and pro-protein convertases for highly pathogenic avian influenza (HPAI) virus, have been reported. Recently, other HA-processing proteases for seasonal IAV and HPAI have been identified in the membrane fraction. These proteases proteolytically activate viral multiplication at the time of viral entry and budding. In addition to the role of host cellular proteases in IAV pathogenicity, IAV infection results in marked upregulation of cellular trypsins and matrix metalloproteinase-9 in various organs and cells, particularly endothelial cells, through induced pro-inflammatory cytokines. These host cellular factors interact with each other as the influenza virus–cytokine–protease cycle, which is the major mechanism that induces vascular hyperpermeability and multiorgan failure in severe influenza. This mini-review discusses the roles of cellular proteases in the pathogenesis of IAV and highlights the molecular mechanisms of upregulation of trypsins as effective targets for the control of IAV infection. This article is part of a Special Issue entitled: Proteolysis 50years after the discovery of lysosome.► Cellular proteases play key roles in virus entry and vascular hyperpermeability. ► Influenza A virus (IAV)-cytokine-protease cycle. ► IAV infection results in marked upregulation of cellular trypsins and MMP-9. ► Processing of IAV hemagglutinin (HA) is a pre-requisite for viral entry into cells. ► Identification of HA processing proteases for highly pathogenic avian IAV.
Keywords: Influenza virus; Highly pathogenic influenza virus; Cytokines; Trypsin; Multiple organ failure; Matrix metalloprotease
Role of host cellular proteases in the pathogenesis of influenza and influenza-induced multiple organ failure by Hiroshi Kido; Yuushi Okumura; Etsuhisa Takahashi; Hai-Yan Pan; Siye Wang; Dengbing Yao; Min Yao; Junji Chida; Mihiro Yano (pp. 186-194).
Influenza A virus (IAV) is one of the most common infectious pathogens in humans. Since the IVA genome does not have the processing protease for the viral hemagglutinin (HA) envelope glycoprotein precursors, entry of this virus into cells and infectious organ tropism of IAV are primarily determined by host cellular trypsin-type HA processing proteases. Several secretion-type HA processing proteases for seasonal IAV in the airway, and ubiquitously expressed furin and pro-protein convertases for highly pathogenic avian influenza (HPAI) virus, have been reported. Recently, other HA-processing proteases for seasonal IAV and HPAI have been identified in the membrane fraction. These proteases proteolytically activate viral multiplication at the time of viral entry and budding. In addition to the role of host cellular proteases in IAV pathogenicity, IAV infection results in marked upregulation of cellular trypsins and matrix metalloproteinase-9 in various organs and cells, particularly endothelial cells, through induced pro-inflammatory cytokines. These host cellular factors interact with each other as the influenza virus–cytokine–protease cycle, which is the major mechanism that induces vascular hyperpermeability and multiorgan failure in severe influenza. This mini-review discusses the roles of cellular proteases in the pathogenesis of IAV and highlights the molecular mechanisms of upregulation of trypsins as effective targets for the control of IAV infection. This article is part of a Special Issue entitled: Proteolysis 50years after the discovery of lysosome.► Cellular proteases play key roles in virus entry and vascular hyperpermeability. ► Influenza A virus (IAV)-cytokine-protease cycle. ► IAV infection results in marked upregulation of cellular trypsins and MMP-9. ► Processing of IAV hemagglutinin (HA) is a pre-requisite for viral entry into cells. ► Identification of HA processing proteases for highly pathogenic avian IAV.
Keywords: Influenza virus; Highly pathogenic influenza virus; Cytokines; Trypsin; Multiple organ failure; Matrix metalloprotease
Role of host cellular proteases in the pathogenesis of influenza and influenza-induced multiple organ failure by Hiroshi Kido; Yuushi Okumura; Etsuhisa Takahashi; Hai-Yan Pan; Siye Wang; Dengbing Yao; Min Yao; Junji Chida; Mihiro Yano (pp. 186-194).
Influenza A virus (IAV) is one of the most common infectious pathogens in humans. Since the IVA genome does not have the processing protease for the viral hemagglutinin (HA) envelope glycoprotein precursors, entry of this virus into cells and infectious organ tropism of IAV are primarily determined by host cellular trypsin-type HA processing proteases. Several secretion-type HA processing proteases for seasonal IAV in the airway, and ubiquitously expressed furin and pro-protein convertases for highly pathogenic avian influenza (HPAI) virus, have been reported. Recently, other HA-processing proteases for seasonal IAV and HPAI have been identified in the membrane fraction. These proteases proteolytically activate viral multiplication at the time of viral entry and budding. In addition to the role of host cellular proteases in IAV pathogenicity, IAV infection results in marked upregulation of cellular trypsins and matrix metalloproteinase-9 in various organs and cells, particularly endothelial cells, through induced pro-inflammatory cytokines. These host cellular factors interact with each other as the influenza virus–cytokine–protease cycle, which is the major mechanism that induces vascular hyperpermeability and multiorgan failure in severe influenza. This mini-review discusses the roles of cellular proteases in the pathogenesis of IAV and highlights the molecular mechanisms of upregulation of trypsins as effective targets for the control of IAV infection. This article is part of a Special Issue entitled: Proteolysis 50years after the discovery of lysosome.► Cellular proteases play key roles in virus entry and vascular hyperpermeability. ► Influenza A virus (IAV)-cytokine-protease cycle. ► IAV infection results in marked upregulation of cellular trypsins and MMP-9. ► Processing of IAV hemagglutinin (HA) is a pre-requisite for viral entry into cells. ► Identification of HA processing proteases for highly pathogenic avian IAV.
Keywords: Influenza virus; Highly pathogenic influenza virus; Cytokines; Trypsin; Multiple organ failure; Matrix metalloprotease
The peptidases of Trypanosoma cruzi: Digestive enzymes, virulence factors, and mediators of autophagy and programmed cell death by Vanina E. Alvarez; Gabriela T. Niemirowicz; Juan J. Cazzulo (pp. 195-206).
Trypanosoma cruzi, the agent of the American Trypanosomiasis, Chagas disease, contains cysteine, serine, threonine, aspartyl and metallo peptidases. The most abundant among these enzymes is cruzipain, a cysteine proteinase expressed as a mixture of isoforms, some of them membrane-bound. The enzyme is an immunodominant antigen in human chronic Chagas disease and seems to be important in the host/parasite relationship. Inhibitors of cruzipain kill the parasite and cure infected mice, thus validating the enzyme as a very promising target for the development of new drugs against the disease. In addition, a 30kDa cathepsin B-like enzyme, two metacaspases and two autophagins have been described. Serine peptidases described in the parasite include oligopeptidase B, a member of the prolyl oligopeptidase family involved in Ca2+-signaling during mammalian cell invasion; a prolyl endopeptidase (Tc80), against which inhibitors are being developed, and a lysosomal serine carboxypeptidase. Metallopeptidases homologous to the gp63 of Leishmania spp. are present, as well as two metallocarboxypeptidases belonging to the M32 family, previously found only in prokaryotes. The proteasome has properties similar to those of other eukaryotes, and its inhibition by lactacystin blocks some differentiation steps in the life cycle of the parasite. This article is part of a Special Issue entitled: Proteolysis 50 years after the discovery of lysosome.► The Trypanosoma cruzi Genome Project predicts peptidases from all catalytic classes. ► However, the chymotrypsin and pepsin families seem to be absent. ► The major cysteine proteinase, cruzipain, is a virulence factor for the parasite. ► Two S9 serine peptidases are also potential targets for chemotherapy. ► T. cruzi has two M32 peptidases, absent so far in all other eukaryotic genomes.
Keywords: Abbreviations; CPs; cysteine proteinases; SPs; serine proteinases; MPs; metalloproteinases; APs; aspartyl proteinases; 20S and 26S proteasome: proteasome oligomers with a sedimentation coefficient of 20S and 26S; respectively; Z; N; -benzyloxycarbonyl; NHMec; amidomethyl coumarine; E-64; trans; -epoxy succinyl amido (4-guanidino) butane; TLCK; N; - α-tosyl-lysyl-chloromethylketone; MHC; major histocompatibility complex; C-T; C-terminal domain of cruzipain; Boc; N; -; t; -butyloxycarbonyl; pNA; p; -nitroanilide; PCR; polymerase chain reaction; gp63; Leishmania; surface proteinase (leishmanolysin); POP Tc80; prolylendopeptidase Tc80 (collagenase); Tc; SCP; T. cruzi; serine carboxypeptidase; Tc; MCP-1 and; Tc; MCP-2; T. cruzi; metallocarboxypeptidase; BbCI; Bauhinia bauhinioides; cysteine protease inhibitor; PCD; programmed cell death; PE; phosphatidylethanolamine Trypanosoma cruzi; Chagas disease; Peptidases; Cruzipain; Metacaspases; Autophagins
The peptidases of Trypanosoma cruzi: Digestive enzymes, virulence factors, and mediators of autophagy and programmed cell death by Vanina E. Alvarez; Gabriela T. Niemirowicz; Juan J. Cazzulo (pp. 195-206).
Trypanosoma cruzi, the agent of the American Trypanosomiasis, Chagas disease, contains cysteine, serine, threonine, aspartyl and metallo peptidases. The most abundant among these enzymes is cruzipain, a cysteine proteinase expressed as a mixture of isoforms, some of them membrane-bound. The enzyme is an immunodominant antigen in human chronic Chagas disease and seems to be important in the host/parasite relationship. Inhibitors of cruzipain kill the parasite and cure infected mice, thus validating the enzyme as a very promising target for the development of new drugs against the disease. In addition, a 30kDa cathepsin B-like enzyme, two metacaspases and two autophagins have been described. Serine peptidases described in the parasite include oligopeptidase B, a member of the prolyl oligopeptidase family involved in Ca2+-signaling during mammalian cell invasion; a prolyl endopeptidase (Tc80), against which inhibitors are being developed, and a lysosomal serine carboxypeptidase. Metallopeptidases homologous to the gp63 of Leishmania spp. are present, as well as two metallocarboxypeptidases belonging to the M32 family, previously found only in prokaryotes. The proteasome has properties similar to those of other eukaryotes, and its inhibition by lactacystin blocks some differentiation steps in the life cycle of the parasite. This article is part of a Special Issue entitled: Proteolysis 50 years after the discovery of lysosome.► The Trypanosoma cruzi Genome Project predicts peptidases from all catalytic classes. ► However, the chymotrypsin and pepsin families seem to be absent. ► The major cysteine proteinase, cruzipain, is a virulence factor for the parasite. ► Two S9 serine peptidases are also potential targets for chemotherapy. ► T. cruzi has two M32 peptidases, absent so far in all other eukaryotic genomes.
Keywords: Abbreviations; CPs; cysteine proteinases; SPs; serine proteinases; MPs; metalloproteinases; APs; aspartyl proteinases; 20S and 26S proteasome: proteasome oligomers with a sedimentation coefficient of 20S and 26S; respectively; Z; N; -benzyloxycarbonyl; NHMec; amidomethyl coumarine; E-64; trans; -epoxy succinyl amido (4-guanidino) butane; TLCK; N; - α-tosyl-lysyl-chloromethylketone; MHC; major histocompatibility complex; C-T; C-terminal domain of cruzipain; Boc; N; -; t; -butyloxycarbonyl; pNA; p; -nitroanilide; PCR; polymerase chain reaction; gp63; Leishmania; surface proteinase (leishmanolysin); POP Tc80; prolylendopeptidase Tc80 (collagenase); Tc; SCP; T. cruzi; serine carboxypeptidase; Tc; MCP-1 and; Tc; MCP-2; T. cruzi; metallocarboxypeptidase; BbCI; Bauhinia bauhinioides; cysteine protease inhibitor; PCD; programmed cell death; PE; phosphatidylethanolamine Trypanosoma cruzi; Chagas disease; Peptidases; Cruzipain; Metacaspases; Autophagins
The peptidases of Trypanosoma cruzi: Digestive enzymes, virulence factors, and mediators of autophagy and programmed cell death by Vanina E. Alvarez; Gabriela T. Niemirowicz; Juan J. Cazzulo (pp. 195-206).
Trypanosoma cruzi, the agent of the American Trypanosomiasis, Chagas disease, contains cysteine, serine, threonine, aspartyl and metallo peptidases. The most abundant among these enzymes is cruzipain, a cysteine proteinase expressed as a mixture of isoforms, some of them membrane-bound. The enzyme is an immunodominant antigen in human chronic Chagas disease and seems to be important in the host/parasite relationship. Inhibitors of cruzipain kill the parasite and cure infected mice, thus validating the enzyme as a very promising target for the development of new drugs against the disease. In addition, a 30kDa cathepsin B-like enzyme, two metacaspases and two autophagins have been described. Serine peptidases described in the parasite include oligopeptidase B, a member of the prolyl oligopeptidase family involved in Ca2+-signaling during mammalian cell invasion; a prolyl endopeptidase (Tc80), against which inhibitors are being developed, and a lysosomal serine carboxypeptidase. Metallopeptidases homologous to the gp63 of Leishmania spp. are present, as well as two metallocarboxypeptidases belonging to the M32 family, previously found only in prokaryotes. The proteasome has properties similar to those of other eukaryotes, and its inhibition by lactacystin blocks some differentiation steps in the life cycle of the parasite. This article is part of a Special Issue entitled: Proteolysis 50 years after the discovery of lysosome.► The Trypanosoma cruzi Genome Project predicts peptidases from all catalytic classes. ► However, the chymotrypsin and pepsin families seem to be absent. ► The major cysteine proteinase, cruzipain, is a virulence factor for the parasite. ► Two S9 serine peptidases are also potential targets for chemotherapy. ► T. cruzi has two M32 peptidases, absent so far in all other eukaryotic genomes.
Keywords: Abbreviations; CPs; cysteine proteinases; SPs; serine proteinases; MPs; metalloproteinases; APs; aspartyl proteinases; 20S and 26S proteasome: proteasome oligomers with a sedimentation coefficient of 20S and 26S; respectively; Z; N; -benzyloxycarbonyl; NHMec; amidomethyl coumarine; E-64; trans; -epoxy succinyl amido (4-guanidino) butane; TLCK; N; - α-tosyl-lysyl-chloromethylketone; MHC; major histocompatibility complex; C-T; C-terminal domain of cruzipain; Boc; N; -; t; -butyloxycarbonyl; pNA; p; -nitroanilide; PCR; polymerase chain reaction; gp63; Leishmania; surface proteinase (leishmanolysin); POP Tc80; prolylendopeptidase Tc80 (collagenase); Tc; SCP; T. cruzi; serine carboxypeptidase; Tc; MCP-1 and; Tc; MCP-2; T. cruzi; metallocarboxypeptidase; BbCI; Bauhinia bauhinioides; cysteine protease inhibitor; PCD; programmed cell death; PE; phosphatidylethanolamine Trypanosoma cruzi; Chagas disease; Peptidases; Cruzipain; Metacaspases; Autophagins
Structural studies of vacuolar plasmepsins by Prasenjit Bhaumik; Alla Gustchina; Alexander Wlodawer (pp. 207-223).
Plasmepsins (PMs) are pepsin-like aspartic proteases present in different species of parasite Plasmodium. Four Plasmodium spp. ( P. vivax, P. ovale, P. malariae, and the most lethal P. falciparum) are mainly responsible for causing human malaria that affects millions worldwide. Due to the complexity and rate of parasite mutation coupled with regional variations, and the emergence of P. falciparum strains which are resistant to antimalarial agents such as chloroquine and sulfadoxine/pyrimethamine, there is constant pressure to find new and lasting chemotherapeutic drug therapies. Since many proteases represent therapeutic targets and PMs have been shown to play an important role in the survival of parasite, these enzymes have recently been identified as promising targets for the development of novel antimalarial drugs. The genome of P. falciparum encodes 10 PMs (PMI, PMII, PMIV-X and histo-aspartic protease (HAP)), 4 of which (PMI, PMII, PMIV and HAP) reside within the food vacuole, are directly involved in degradation of human hemoglobin, and share 50–79% amino acid sequence identity. This review focuses on structural studies of only these four enzymes, including their orthologs in other Plasmodium spp.. Almost all original crystallographic studies were performed with PMII, but more recent work on PMIV, PMI, and HAP resulted in a more complete picture of the structure–function relationship of vacuolar PMs. Many structures of inhibitor complexes of vacuolar plasmepsins, as well as their zymogens, have been reported in the last 15years. Information gained by such studies will be helpful for the development of better inhibitors that could become a new class of potent antimalarial drugs. This article is part of a Special Issue entitled: Proteolysis 50years after the discovery of lysosome.Display Omitted► Plasmepsins are aspartic proteases encoded by parasite Plasmodium. ► Since these parasites cause malaria, plasmepsins are targets for drug design. ► Four plasmepsins are found in food vacuole of Plasmodium falciparum. ► Crystal structures of all four enzymes have been solved. ► Data on structure and inhibition are summarized here.
Keywords: Aspartic protease; Malaria; Crystal structure; Plasmepsin; Inhibitors
Structural studies of vacuolar plasmepsins by Prasenjit Bhaumik; Alla Gustchina; Alexander Wlodawer (pp. 207-223).
Plasmepsins (PMs) are pepsin-like aspartic proteases present in different species of parasite Plasmodium. Four Plasmodium spp. ( P. vivax, P. ovale, P. malariae, and the most lethal P. falciparum) are mainly responsible for causing human malaria that affects millions worldwide. Due to the complexity and rate of parasite mutation coupled with regional variations, and the emergence of P. falciparum strains which are resistant to antimalarial agents such as chloroquine and sulfadoxine/pyrimethamine, there is constant pressure to find new and lasting chemotherapeutic drug therapies. Since many proteases represent therapeutic targets and PMs have been shown to play an important role in the survival of parasite, these enzymes have recently been identified as promising targets for the development of novel antimalarial drugs. The genome of P. falciparum encodes 10 PMs (PMI, PMII, PMIV-X and histo-aspartic protease (HAP)), 4 of which (PMI, PMII, PMIV and HAP) reside within the food vacuole, are directly involved in degradation of human hemoglobin, and share 50–79% amino acid sequence identity. This review focuses on structural studies of only these four enzymes, including their orthologs in other Plasmodium spp.. Almost all original crystallographic studies were performed with PMII, but more recent work on PMIV, PMI, and HAP resulted in a more complete picture of the structure–function relationship of vacuolar PMs. Many structures of inhibitor complexes of vacuolar plasmepsins, as well as their zymogens, have been reported in the last 15years. Information gained by such studies will be helpful for the development of better inhibitors that could become a new class of potent antimalarial drugs. This article is part of a Special Issue entitled: Proteolysis 50years after the discovery of lysosome.Display Omitted► Plasmepsins are aspartic proteases encoded by parasite Plasmodium. ► Since these parasites cause malaria, plasmepsins are targets for drug design. ► Four plasmepsins are found in food vacuole of Plasmodium falciparum. ► Crystal structures of all four enzymes have been solved. ► Data on structure and inhibition are summarized here.
Keywords: Aspartic protease; Malaria; Crystal structure; Plasmepsin; Inhibitors
Structural studies of vacuolar plasmepsins by Prasenjit Bhaumik; Alla Gustchina; Alexander Wlodawer (pp. 207-223).
Plasmepsins (PMs) are pepsin-like aspartic proteases present in different species of parasite Plasmodium. Four Plasmodium spp. ( P. vivax, P. ovale, P. malariae, and the most lethal P. falciparum) are mainly responsible for causing human malaria that affects millions worldwide. Due to the complexity and rate of parasite mutation coupled with regional variations, and the emergence of P. falciparum strains which are resistant to antimalarial agents such as chloroquine and sulfadoxine/pyrimethamine, there is constant pressure to find new and lasting chemotherapeutic drug therapies. Since many proteases represent therapeutic targets and PMs have been shown to play an important role in the survival of parasite, these enzymes have recently been identified as promising targets for the development of novel antimalarial drugs. The genome of P. falciparum encodes 10 PMs (PMI, PMII, PMIV-X and histo-aspartic protease (HAP)), 4 of which (PMI, PMII, PMIV and HAP) reside within the food vacuole, are directly involved in degradation of human hemoglobin, and share 50–79% amino acid sequence identity. This review focuses on structural studies of only these four enzymes, including their orthologs in other Plasmodium spp.. Almost all original crystallographic studies were performed with PMII, but more recent work on PMIV, PMI, and HAP resulted in a more complete picture of the structure–function relationship of vacuolar PMs. Many structures of inhibitor complexes of vacuolar plasmepsins, as well as their zymogens, have been reported in the last 15years. Information gained by such studies will be helpful for the development of better inhibitors that could become a new class of potent antimalarial drugs. This article is part of a Special Issue entitled: Proteolysis 50years after the discovery of lysosome.Display Omitted► Plasmepsins are aspartic proteases encoded by parasite Plasmodium. ► Since these parasites cause malaria, plasmepsins are targets for drug design. ► Four plasmepsins are found in food vacuole of Plasmodium falciparum. ► Crystal structures of all four enzymes have been solved. ► Data on structure and inhibition are summarized here.
Keywords: Aspartic protease; Malaria; Crystal structure; Plasmepsin; Inhibitors
Calpains — An elaborate proteolytic system by Yasuko Ono; Hiroyuki Sorimachi (pp. 224-236).
Calpain is an intracellular Ca2+-dependent cysteine protease (EC 3.4.22.17; Clan CA, family C02). Recent expansion of sequence data across the species definitively shows that calpain has been present throughout evolution; calpains are found in almost all eukaryotes and some bacteria, but not in archaebacteria. Fifteen genes within the human genome encode a calpain-like protease domain. Interestingly, some human calpains, particularly those with non-classical domain structures, are very similar to calpain homologs identified in evolutionarily distant organisms. Three-dimensional structural analyses have helped to identify calpain's unique mechanism of activation; the calpain protease domain comprises two core domains that fuse to form a functional protease only when bound to Ca2+ via well-conserved amino acids. This finding highlights the mechanistic characteristics shared by the numerous calpain homologs, despite the fact that they have divergent domain structures. In other words, calpains function through the same mechanism but are regulated independently. This article reviews the recent progress in calpain research, focusing on those studies that have helped to elucidate its mechanism of action. This article is part of a Special Issue entitled: Proteolysis 50years after the discovery of lysosome.► Calpains comprise an evolutionarily distinct group of cysteine proteases. ► Genetic approaches using various systems have identified several different components involved in calpain regulation. ► Structural studies have identified the mechanisms underlying the Ca2+-regulated activation of calpain. ► The conserved and unique structural features of calpains are important topics for future study.
Keywords: Abbreviations; aa; amino acid(s); C2; C2 domain; C2L; C2 domain-like domain; CAPN; calpain; CysPc; calpain-like cysteine protease sequence motif defined in the conserved domain database at the National Center for Biotechnology Information (cd00044); PEF; penta EF-hand; RMSD; root-mean-square deviationCalpain; Calcium ion; Protease; Skeletal muscle; Gastric system; Proteolysis
Calpains — An elaborate proteolytic system by Yasuko Ono; Hiroyuki Sorimachi (pp. 224-236).
Calpain is an intracellular Ca2+-dependent cysteine protease (EC 3.4.22.17; Clan CA, family C02). Recent expansion of sequence data across the species definitively shows that calpain has been present throughout evolution; calpains are found in almost all eukaryotes and some bacteria, but not in archaebacteria. Fifteen genes within the human genome encode a calpain-like protease domain. Interestingly, some human calpains, particularly those with non-classical domain structures, are very similar to calpain homologs identified in evolutionarily distant organisms. Three-dimensional structural analyses have helped to identify calpain's unique mechanism of activation; the calpain protease domain comprises two core domains that fuse to form a functional protease only when bound to Ca2+ via well-conserved amino acids. This finding highlights the mechanistic characteristics shared by the numerous calpain homologs, despite the fact that they have divergent domain structures. In other words, calpains function through the same mechanism but are regulated independently. This article reviews the recent progress in calpain research, focusing on those studies that have helped to elucidate its mechanism of action. This article is part of a Special Issue entitled: Proteolysis 50years after the discovery of lysosome.► Calpains comprise an evolutionarily distinct group of cysteine proteases. ► Genetic approaches using various systems have identified several different components involved in calpain regulation. ► Structural studies have identified the mechanisms underlying the Ca2+-regulated activation of calpain. ► The conserved and unique structural features of calpains are important topics for future study.
Keywords: Abbreviations; aa; amino acid(s); C2; C2 domain; C2L; C2 domain-like domain; CAPN; calpain; CysPc; calpain-like cysteine protease sequence motif defined in the conserved domain database at the National Center for Biotechnology Information (cd00044); PEF; penta EF-hand; RMSD; root-mean-square deviationCalpain; Calcium ion; Protease; Skeletal muscle; Gastric system; Proteolysis
Calpains — An elaborate proteolytic system by Yasuko Ono; Hiroyuki Sorimachi (pp. 224-236).
Calpain is an intracellular Ca2+-dependent cysteine protease (EC 3.4.22.17; Clan CA, family C02). Recent expansion of sequence data across the species definitively shows that calpain has been present throughout evolution; calpains are found in almost all eukaryotes and some bacteria, but not in archaebacteria. Fifteen genes within the human genome encode a calpain-like protease domain. Interestingly, some human calpains, particularly those with non-classical domain structures, are very similar to calpain homologs identified in evolutionarily distant organisms. Three-dimensional structural analyses have helped to identify calpain's unique mechanism of activation; the calpain protease domain comprises two core domains that fuse to form a functional protease only when bound to Ca2+ via well-conserved amino acids. This finding highlights the mechanistic characteristics shared by the numerous calpain homologs, despite the fact that they have divergent domain structures. In other words, calpains function through the same mechanism but are regulated independently. This article reviews the recent progress in calpain research, focusing on those studies that have helped to elucidate its mechanism of action. This article is part of a Special Issue entitled: Proteolysis 50years after the discovery of lysosome.► Calpains comprise an evolutionarily distinct group of cysteine proteases. ► Genetic approaches using various systems have identified several different components involved in calpain regulation. ► Structural studies have identified the mechanisms underlying the Ca2+-regulated activation of calpain. ► The conserved and unique structural features of calpains are important topics for future study.
Keywords: Abbreviations; aa; amino acid(s); C2; C2 domain; C2L; C2 domain-like domain; CAPN; calpain; CysPc; calpain-like cysteine protease sequence motif defined in the conserved domain database at the National Center for Biotechnology Information (cd00044); PEF; penta EF-hand; RMSD; root-mean-square deviationCalpain; Calcium ion; Protease; Skeletal muscle; Gastric system; Proteolysis
Structure and function of tripeptidyl peptidase II, a giant cytosolic protease by Beate Rockel; Klaus O. Kopec; Andrei N. Lupas; Wolfgang Baumeister (pp. 237-245).
Tripeptidyl peptidase II is the largest known eukaryotic peptidase. It has been described as a multi-purpose peptidase, which, in addition to its house-keeping function in intracellular protein degradation, plays a role in several vital cellular processes such as antigen processing, apoptosis, or cell division, and is involved in diseases like muscle wasting, obesity, and in cancer. Biochemical studies and bioinformatics have identified TPPII as a subtilase, but its structure is very unusual: it forms a large homooligomeric complex (6MDa) with a spindle-like shape. Recently, the high-resolution structure of TPPII homodimers (300kDa) was solved and a hybrid structure of the holocomplex built of 20 dimers was obtained by docking it into the EM-density. Here, we summarize our current knowledge about TPPII with a focus on structural aspects. This article is part of a Special Issue entitled: Proteolysis 50years after the discovery of lysosome.► The current knowledge about tripeptidyl peptidase II is summarized with a focus on structural aspects. ► The functional relevance of the quaternary structure of tripeptidyl peptidase II is discussed. ► The evolution of tripeptidyl peptidase II is investigated using structural and sequence comparisons as well as clustering methods.
Keywords: Tripeptidyl peptidase II; Cytosolic proteolysis; Hybrid structure; Protein evolution
Structure and function of tripeptidyl peptidase II, a giant cytosolic protease by Beate Rockel; Klaus O. Kopec; Andrei N. Lupas; Wolfgang Baumeister (pp. 237-245).
Tripeptidyl peptidase II is the largest known eukaryotic peptidase. It has been described as a multi-purpose peptidase, which, in addition to its house-keeping function in intracellular protein degradation, plays a role in several vital cellular processes such as antigen processing, apoptosis, or cell division, and is involved in diseases like muscle wasting, obesity, and in cancer. Biochemical studies and bioinformatics have identified TPPII as a subtilase, but its structure is very unusual: it forms a large homooligomeric complex (6MDa) with a spindle-like shape. Recently, the high-resolution structure of TPPII homodimers (300kDa) was solved and a hybrid structure of the holocomplex built of 20 dimers was obtained by docking it into the EM-density. Here, we summarize our current knowledge about TPPII with a focus on structural aspects. This article is part of a Special Issue entitled: Proteolysis 50years after the discovery of lysosome.► The current knowledge about tripeptidyl peptidase II is summarized with a focus on structural aspects. ► The functional relevance of the quaternary structure of tripeptidyl peptidase II is discussed. ► The evolution of tripeptidyl peptidase II is investigated using structural and sequence comparisons as well as clustering methods.
Keywords: Tripeptidyl peptidase II; Cytosolic proteolysis; Hybrid structure; Protein evolution
Structure and function of tripeptidyl peptidase II, a giant cytosolic protease by Beate Rockel; Klaus O. Kopec; Andrei N. Lupas; Wolfgang Baumeister (pp. 237-245).
Tripeptidyl peptidase II is the largest known eukaryotic peptidase. It has been described as a multi-purpose peptidase, which, in addition to its house-keeping function in intracellular protein degradation, plays a role in several vital cellular processes such as antigen processing, apoptosis, or cell division, and is involved in diseases like muscle wasting, obesity, and in cancer. Biochemical studies and bioinformatics have identified TPPII as a subtilase, but its structure is very unusual: it forms a large homooligomeric complex (6MDa) with a spindle-like shape. Recently, the high-resolution structure of TPPII homodimers (300kDa) was solved and a hybrid structure of the holocomplex built of 20 dimers was obtained by docking it into the EM-density. Here, we summarize our current knowledge about TPPII with a focus on structural aspects. This article is part of a Special Issue entitled: Proteolysis 50years after the discovery of lysosome.► The current knowledge about tripeptidyl peptidase II is summarized with a focus on structural aspects. ► The functional relevance of the quaternary structure of tripeptidyl peptidase II is discussed. ► The evolution of tripeptidyl peptidase II is investigated using structural and sequence comparisons as well as clustering methods.
Keywords: Tripeptidyl peptidase II; Cytosolic proteolysis; Hybrid structure; Protein evolution
Thrombin plasticity by James A. Huntington (pp. 246-252).
Thrombin is the final protease generated in the blood coagulation cascade. It has multiple substrates and cofactors, and serves both pro- and anti-coagulant functions. How thrombin activity is directed throughout the evolution of a clot and the role of conformational change in determining thrombin specificity are issues that lie at the heart of the haemostatic balance. Over the last 20years there have been a great number of studies supporting the idea that thrombin is an allosteric enzyme that can exist in two conformations differing in activity and specificity. However, recent work has shown that thrombin in its unliganded state is inherently flexible in regions that are important for activity. The effect of flexibility on activity is discussed in this review in context of the zymogen-to-protease conformational transition. Understanding thrombin function in terms of ‘plasticity’ provides a new conceptual framework for understanding regulation of enzyme activity in general. This article is part of a Special Issue entitled: Proteolysis 50 years after the discovery of lysosome.► This review summarises recent work on thrombin structure and function. ► Crystallography and NMR studies show that thrombin is a highly flexible enzyme. ► This plasticity is important for its function. ► Flexibility is related to the zymogen-to-protease conformational change. ► Flexibility may be a general concept for regulatory enzymes.
Keywords: Haemostasis; Protease; Regulation; Thrombosis; Zymogen
Thrombin plasticity by James A. Huntington (pp. 246-252).
Thrombin is the final protease generated in the blood coagulation cascade. It has multiple substrates and cofactors, and serves both pro- and anti-coagulant functions. How thrombin activity is directed throughout the evolution of a clot and the role of conformational change in determining thrombin specificity are issues that lie at the heart of the haemostatic balance. Over the last 20years there have been a great number of studies supporting the idea that thrombin is an allosteric enzyme that can exist in two conformations differing in activity and specificity. However, recent work has shown that thrombin in its unliganded state is inherently flexible in regions that are important for activity. The effect of flexibility on activity is discussed in this review in context of the zymogen-to-protease conformational transition. Understanding thrombin function in terms of ‘plasticity’ provides a new conceptual framework for understanding regulation of enzyme activity in general. This article is part of a Special Issue entitled: Proteolysis 50 years after the discovery of lysosome.► This review summarises recent work on thrombin structure and function. ► Crystallography and NMR studies show that thrombin is a highly flexible enzyme. ► This plasticity is important for its function. ► Flexibility is related to the zymogen-to-protease conformational change. ► Flexibility may be a general concept for regulatory enzymes.
Keywords: Haemostasis; Protease; Regulation; Thrombosis; Zymogen
Thrombin plasticity by James A. Huntington (pp. 246-252).
Thrombin is the final protease generated in the blood coagulation cascade. It has multiple substrates and cofactors, and serves both pro- and anti-coagulant functions. How thrombin activity is directed throughout the evolution of a clot and the role of conformational change in determining thrombin specificity are issues that lie at the heart of the haemostatic balance. Over the last 20years there have been a great number of studies supporting the idea that thrombin is an allosteric enzyme that can exist in two conformations differing in activity and specificity. However, recent work has shown that thrombin in its unliganded state is inherently flexible in regions that are important for activity. The effect of flexibility on activity is discussed in this review in context of the zymogen-to-protease conformational transition. Understanding thrombin function in terms of ‘plasticity’ provides a new conceptual framework for understanding regulation of enzyme activity in general. This article is part of a Special Issue entitled: Proteolysis 50 years after the discovery of lysosome.► This review summarises recent work on thrombin structure and function. ► Crystallography and NMR studies show that thrombin is a highly flexible enzyme. ► This plasticity is important for its function. ► Flexibility is related to the zymogen-to-protease conformational change. ► Flexibility may be a general concept for regulatory enzymes.
Keywords: Haemostasis; Protease; Regulation; Thrombosis; Zymogen
Mannose-binding lectin serine proteases and associated proteins of the lectin pathway of complement: Two genes, five proteins and many functions? by Tang Yongqing; Nicole Drentin; Renee C. Duncan; Lakshmi C. Wijeyewickrema; Robert N. Pike (pp. 253-262).
The lectin pathway of the complement system is activated following the binding of carbohydrate-based ligands by recognition molecules such as mannose-binding lectin (MBL) or ficolins. Engagement of the recognition molecules causes activation of associated MBL-associated serine proteases or MASPs, which in turn activate downstream complement molecules to activate the system. Two MASP genes are alternatively spliced during expression to yield 5 proteins, including three proteases (MASP-1, -2 and -3) and two truncated proteins, MAp19 and MAp44. Here we discuss what is currently known about these proteins in terms of their structure and function. MASP-2 is autoactivated following the initial binding events of the pathway and is able to subsequently activate the C4 and C2 substrates required to activate the rest of the pathway. MASP-1 is able to augment MASP-2 activation, but also appears to play other roles, although the physiological significance of these is not yet clear. The roles of the truncated Map19 and Map44 proteins and the MASP-3 protease are currently unknown. The proteases form an interesting sub-family of proteins that clearly should be the focus of future research in order to establish their biological roles.This article is part of a Special Issue entitled: Proteolysis 50years after the discovery of lysosome.
Keywords: Complement; Lectin pathway; Mannose-binding lectin associated serine protease
Mannose-binding lectin serine proteases and associated proteins of the lectin pathway of complement: Two genes, five proteins and many functions? by Tang Yongqing; Nicole Drentin; Renee C. Duncan; Lakshmi C. Wijeyewickrema; Robert N. Pike (pp. 253-262).
The lectin pathway of the complement system is activated following the binding of carbohydrate-based ligands by recognition molecules such as mannose-binding lectin (MBL) or ficolins. Engagement of the recognition molecules causes activation of associated MBL-associated serine proteases or MASPs, which in turn activate downstream complement molecules to activate the system. Two MASP genes are alternatively spliced during expression to yield 5 proteins, including three proteases (MASP-1, -2 and -3) and two truncated proteins, MAp19 and MAp44. Here we discuss what is currently known about these proteins in terms of their structure and function. MASP-2 is autoactivated following the initial binding events of the pathway and is able to subsequently activate the C4 and C2 substrates required to activate the rest of the pathway. MASP-1 is able to augment MASP-2 activation, but also appears to play other roles, although the physiological significance of these is not yet clear. The roles of the truncated Map19 and Map44 proteins and the MASP-3 protease are currently unknown. The proteases form an interesting sub-family of proteins that clearly should be the focus of future research in order to establish their biological roles.This article is part of a Special Issue entitled: Proteolysis 50years after the discovery of lysosome.
Keywords: Complement; Lectin pathway; Mannose-binding lectin associated serine protease
Mannose-binding lectin serine proteases and associated proteins of the lectin pathway of complement: Two genes, five proteins and many functions? by Tang Yongqing; Nicole Drentin; Renee C. Duncan; Lakshmi C. Wijeyewickrema; Robert N. Pike (pp. 253-262).
The lectin pathway of the complement system is activated following the binding of carbohydrate-based ligands by recognition molecules such as mannose-binding lectin (MBL) or ficolins. Engagement of the recognition molecules causes activation of associated MBL-associated serine proteases or MASPs, which in turn activate downstream complement molecules to activate the system. Two MASP genes are alternatively spliced during expression to yield 5 proteins, including three proteases (MASP-1, -2 and -3) and two truncated proteins, MAp19 and MAp44. Here we discuss what is currently known about these proteins in terms of their structure and function. MASP-2 is autoactivated following the initial binding events of the pathway and is able to subsequently activate the C4 and C2 substrates required to activate the rest of the pathway. MASP-1 is able to augment MASP-2 activation, but also appears to play other roles, although the physiological significance of these is not yet clear. The roles of the truncated Map19 and Map44 proteins and the MASP-3 protease are currently unknown. The proteases form an interesting sub-family of proteins that clearly should be the focus of future research in order to establish their biological roles.This article is part of a Special Issue entitled: Proteolysis 50years after the discovery of lysosome.
Keywords: Complement; Lectin pathway; Mannose-binding lectin associated serine protease