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BBA - Gene Regulatory Mechanisms (v.1809, #2)
Structure characterization of the 26S proteasome by Ho Min Kim; Yadong Yu; Yifan Cheng (pp. 67-79).
In all eukaryotic cells, 26S proteasome plays an essential role in the process of ATP-dependent protein degradation. In this review, we focus on structure characterization of the 26S proteasome. Although the progress towards a high-resolution structure of the 26S proteasome has been slow, the recently solved structures of various proteasomal subcomplexes have greatly enhanced our understanding of this large machinery. In addition to having an ATP-dependent proteolytic function, the 26S proteasome is also involved in many non-proteolytic cellular activities, which are often mediated by subunits in its 19S regulatory complex. Thus, we include a detailed discussion of the structures of 19S subunits, including proteasomal ATPases, ubiquitin receptors, deubiquitinating enzymes and subunits that contain PCI domain. This article is part of a Special Issue entitled The 26S Proteasome: When degradation is just not enough!
Keywords: 26S proteasome; Structure
Ubiquitin–Proteasome System and mitochondria — Reciprocity by Nurit Livnat-Levanon; Michael H. Glickman (pp. 80-87).
Recently, sporadic links have been published between mitochondria – membrane-confined organelles – and the cytosolic ubiquitin–proteasome system (UPS) for removal of cellular proteins. For example, Fzo1, a mitochondrial outer membrane mitofusin was shown to be ubiquitinated by a ubiquitin ligase, Cdc53MDM30, and degraded by the proteasome. Two additional ubiquitin ligases, MITOL/MARCH-V and MULAN, as well as a deubiquitinating enzyme, Ubp16/USP30, are embedded in mitochondrial outer membranes and participate in mitochondrial dynamics. Defects in mitochondrial morphology or respiration capacity are also reported for mutations in other UPS components such as the Ub ligases Parkin and Rsp5 as well as in proteasome subunits. These examples are likely to reflect a pervasive involvement of UPS in recycling of mitochondria-associated proteins. The flux of imported proteins and the proximity to oxidative phosphorylation results in abundant damaged or misfolded proteins that generate the need for a responsive quality control system. Within the mitochondrial matrix there is a self-contained ATP-dependent system for protein turnover. However at the outer membrane, the UPS may play a corresponding role in recycling either membrane-embedded or imported proteins. In a parallel process, ubiquitination also partakes in selection of damaged mitochondria to the lysozome/vacuole via autophagy. In the reverse direction, components of the UPS are sensitive to cellular REDOX potential, and as such are affected by reactive oxygen species (ROS) generated as a byproduct of mitochondrial respiration. This review will try to address the regulation of mitochondrial morphology and metabolic function by UPS, as well as the reciprocal relationship between aberrant ROS produced by mitochondria and ubiquitination or proteasome activity. This article is part of a Special Issue entitled The 26S Proteasome: When degradation is just not enough!
Keywords: Abbreviations; Ub; ubiquitin; UPS; ubiquitin–proteasome system; mt-DNA; mitochondrial DNA; MOM; mitochondrial outer membrane; MIM; mitochondrial inner membrane; IMS; mitochondrial inter-membrane space; ROS; reactive oxygen species; MAD; mitochondria associated degradation; ERAD; ER associated degradationUbiquitin; Proteasome; SUMO; Mitochondria; Oxidative phosphorylation; Respiration; Reactive oxygen species; Membrane fusion; Membrane dynamics; Autophagy; Mitophagy
The proteasome and its regulatory roles in gene expression by Jaechan Kwak; Jerry L. Workman; Daeyoup Lee (pp. 88-96).
Cumulative evidence indicates that the proteasome, which is mainly known as a protein-degrading machine, is very essential for gene expression. Destructive functions of the proteasome, i.e., ubiquitin-dependent proteolytic activity, are significant for activator localization, activator destruction, co-activator/repressor destruction and PIC disassembly. Non-proteolytic functions of the proteasome are important for recruitment of activators and co-activators to promoters, ubiquitin-dependent histone modification, transcription elongation and possibly maturation of mRNA via the facilitation of mRNA export from the nucleus to the cytoplasm. In this review, we discuss how the proteasome regulates transcription at numerous stages during gene expression. This article is part of a Special Issue entitled The 26S Proteasome: When degradation is just not enough!▸Basic structure of the 26S proteasome complex and its relationship to gene expression. ▸The proteolytic roles played by the 26S proteasome in transcription. ▸Non-proteolytic roles played by the proteasome in transcription.
Keywords: 26S proteasome; 19S regulatory particle; Transcriptional regulation; Chaperone activity; Histone modification; Ubiquitin
Distinct regulatory mechanisms of eukaryotic transcriptional activation by SAGA and TFIID by Sukesh R. Bhaumik (pp. 97-108).
A growing number of human diseases are linked to abnormal gene expression which is largely controlled at the level of transcriptional initiation. The gene-specific activator promotes the initiation of transcription through its interaction with one or more components of the transcriptional initiation machinery, hence leading to stimulated transcriptional initiation or activation. However, all activator proteins do not target the same component(s) of the transcriptional initiation machinery. Rather, they can have different target specificities, and thus, can lead to distinct mechanisms of transcriptional activation. Two such distinct mechanisms of transcriptional activation in yeast are mediated by the SAGA (Spt-Ada-Gcn5-Acetyltransferase) and TFIID (Transcription factor IID) complexes, and are termed as “SAGA-dependent” and “TFIID-dependent” transcriptional activation, respectively. SAGA is the target of the activator in case of SAGA-dependent transcriptional activation, while the targeting of TFIID by the activator leads to TFIID-dependent transcriptional activation. Both the SAGA and TFIID complexes are highly conserved from yeast to human, and play crucial roles in gene activation among eukaryotes. The regulatory mechanisms of eukaryotic transcriptional activation by SAGA and TFIID are discussed here. This article is part of a Special Issue entitled The 26S Proteasome: When degradation is just not enough!► Eukaryotic gene activation.
Keywords: Transcriptional activation; SAGA; TFIID; Activator; TBP; Proteasome; RNA polymerase II
Emerging roles of the 26S proteasome in nuclear hormone receptor-regulated transcription by Brian R. Keppler; Trevor K. Archer; H. Karimi Kinyamu (pp. 109-118).
The mechanisms by which nuclear hormone receptors (NHRs) regulate transcription are highly dynamic and require interplay between a myriad of regulatory protein complexes including the 26S proteasome. Protein degradation is the most well-established role of the proteasome; however, an increasing body of evidence suggests that the 26S proteasome may regulate transcription in proteolytic and nonproteolytic mechanisms. Here we review how these mechanisms may apply to NHR-mediated transcriptional regulation. This article is part of a Special Issue entitled The 26S Proteasome: When degradation is just not enough!► Nuclear hormone receptors are specialized transcriptional regulators that interact directly with chromatin. ► The proteasome regulates NHR-mediated transcription via proteolytic and non-proteolytic mechanisms. ► The proteasome expands NHR transcriptional networks by modulating chromatin plasticity.
Keywords: Proteasome; Nuclear hormone receptor; Transcription; Chromatin
E3 ubiquitin protein ligase, E6-associated protein (E6-AP) regulates PI3K-Akt signaling and prostate cell growth by Sathish Srinivasan; Zafar Nawaz (pp. 119-127).
This study elucidates the role of E6-associated protein, E6-AP (a dual function steroid hormone receptor coactivator and ubiquitin–protein ligase) in the regulation of PI3K-Akt signaling pathway, prostate gland growth and proliferation. Here, we report the generation of transgenic mice and prostate cancer cell line, LNCaP cells that overexpress E6-AP protein. Using these models we show that the levels of total Akt and phosphorylated Akt (active Akt) are increased in E6-AP overexpressing prostate gland and LNCaP cells suggesting that E6-AP regulates the PI3K-Akt signaling pathway. The prostate glands in our transgenic mice are ~20% larger and produce preneoplastic lesions at the age of 18months. Our data also suggest that E6-AP modulates PI3K-Akt signaling pathway by both androgen-independent and -dependent mechanisms. In the androgen-independent mechanism, E6-AP modulates PI3K-Akt signaling by regulating the protein levels of RhoA, a small GTPase, which is a negative regulator of the Akt signaling pathway. Further, we show that E6-AP, a known coactivator of AR, amplifies the androgen-dependent activation of PI3K-Akt signaling pathway. In addition, we show that stable overexpression of E6-AP in prostate cancer cells results in increased cell size and proliferation. Overall our data suggests that E6-AP regulates both the positive and negative modulators of the PI3K-Akt pathway in prostate cells which results in increased prostate cell growth, proliferation and decreased apoptosis.This article is part of a Special Issue entitled The 26S Proteasome: When degradation is just not enough!
Keywords: E6-AP; PI3K-AKT; Androgen receptor; Prostate gland; RhoA
Role of ubiquitin–proteasome-mediated proteolysis in nervous system disease by Ashok N. Hegde; Sudarshan C. Upadhya (pp. 128-140).
Proteolysis by the ubiquitin–proteasome pathway (UPP) is now widely recognized as a molecular mechanism controlling myriad normal functions in the nervous system. Also, this pathway is intimately linked to many diseases and disorders of the brain. Among the diseases connected to the UPP are neurodegenerative disorders such as Alzheimer's, Parkinson's and Huntington's diseases. Perturbation in the UPP is also believed to play a causative role in mental disorders such as Angelman syndrome. The pathology of neurodegenerative diseases is characterized by abnormal deposition of insoluble protein aggregates or inclusion bodies within neurons. The ubiquitinated protein aggregates are believed to result from dysfunction of the UPP or from structural changes in the protein substrates which prevent their recognition and degradation by the UPP. An early effect of abnormal UPP in diseases of the nervous system is likely to be impairment of synaptic function. Here we discuss the UPP and its physiological roles in the nervous system and how alterations in the UPP relate to development of nervous system diseases. This article is part of a Special Issue entitled The 26S Proteasome: When degradation is just not enough!
Keywords: Neurodegenerative disease; Mental disorders; Synaptic plasticity; Therapeutic targets; Alzheimer’s; Parkinson's
The role of the proteasome in heart disease by Yi-Fan Li; Xuejun Wang (pp. 141-149).
Intensive investigations into the pathophysiological significance of the proteasome in the heart did not start until the beginning of the past decade but exciting progress has been made and summarized here as two fronts. First, strong evidence continues to emerge to support a novel hypothesis that proteasome functional insufficiency represents a common pathological phenomenon in a large subset of heart disease, compromises protein quality control in heart muscle cells, and thereby acts as a major pathogenic factor promoting the progression of the subset of heart disease to congestive heart failure. This front is represented by the studies on the ubiquitin–proteasome system (UPS) in cardiac proteinopathy, which have taken advantage of a transgenic mouse model expressing a fluorescence reporter for UPS proteolytic function. Second, pharmacological inhibition of the proteasome has been explored experimentally as a potential therapeutic strategy to intervene on some forms of heart disease, such as pressure-overload cardiac hypertrophy, viral myocarditis, and myocardial ischemic injury. Not only between the two fronts but also within each one, a multitude of inconsistencies and controversies remain to be explained and clarified. At present, the controversy perhaps reflects the sophistication of cardiac proteasomes in terms of the composition, assembly, and regulation, as well as the intricacy and diversity of heart disease in terms of its etiology and pathogenesis. A definitive role of altered proteasome function in the development of various forms of heart disease remains to be established. This article is part of a Special Issue entitled The 26S Proteasome: When degradation is just not enough!►Cardiac proteasomes may differ from those of other tissues/organs. ►Proteasome functional insufficiency is common in many forms of heart disease. ►Proteasome functional insufficiency may play a key role in cardiac pathogenesis. ►Brief proteasome inhibition might be useful to intervene on some cardiac disease. ►Genetic tools are needed to decipher the pathophysiology of cardiac proteasomes.
Keywords: Abbreviations; CHF; congestive heart failure; CryAB; αB-crystallin; CVB3; coxsackie virus B3; D7-des; a 7-amino acid (R172 through E178) deletion mutation of desmin; CryAB; R120G; a missense (R120G) mutation of CryAB; Dox; doxorubicin; DRC; desmin-related cardiomyopathy; ER; endoplasmic reticulum; GFP; green fluorescence protein; GFPdgn; GFP with carboxyl fusion of degron CL1; IPC; ischemia-preconditioning; I/R; ischemia/reperfusion; NFAT; Nuclear factor-activated T cell; PFI; proteasome functional insufficiency; PKA; protein kinase A; PP2A; protein phosphatase 2A; PQC; protein quality control; ROS; reactive oxygen species; TAC; transverse aortic constriction; UPS; ubiquitin–proteasome systemProteasome; Heart disease; Desmin-related cardiomyopathy; Myocardial ischemia; Cardiac hypertrophy; Myocarditis; Diabetes
Proteolytic and non-proteolytic roles of ubiquitin and the ubiquitin proteasome system in transcriptional regulation by Kavita P. Bhat; Susanna F. Greer (pp. 150-155).
The ubiquitin proteasome system (UPS) regulates perhaps the most intriguing balance in all of biology: how cells control protein function and malfunction in order to regulate, and eventually eliminate, the old and error prone while simultaneously synthesizing and orchestrating the new. In light of the growing notion that ubiquitination and the 26S proteasome are central to a multiplicity of diverse cellular functions, we discuss here the proteolytic and non-proteolytic roles of the UPS in regulating pathways ultimately involved in protein synthesis and activity including roles in epigenetics, transcription, and post-translational modifications. This article is part of a Special Issue entitled The 26S Proteasome: When degradation is just not enough!► We discuss proteolytic and non-proteolytic roles of the Ubiquitin Proteasome System. ► Roles of the UPS in epigenetics, transcription, and protein modification are examined. ► UPS regulation of Major Histocompatibility class II and CIITA pIV is highlighted.
Keywords: 19S ATPases; Ubiquitin; Proteasome; CIITA; MHC II