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BBA - Molecular Cell Research (v.1793, #9)

Editorial Board (pp. i).

Autophagy: Evolutionary and pathophysiological insights by Jean-Claude Martinou; Guido Kroemer (pp. 1395-1396).

Function and regulation of macroautophagy in plants by Diane C. Bassham ⁎ (pp. 1397-1403).

The plant vacuole is a major site for the degradation of macromolecules, which are transferred from the cytoplasm by autophagy via double-membrane vesicles termed autophagosomes. Autophagy functions at a basal level under normal growth conditions and is induced during senescence and upon exposure to stress conditions to recycle nutrients or degrade damaged proteins and organelles. Autophagy is also required for the regulation of programmed cell death as a response to pathogen infection and possibly during certain developmental processes. Little is known about how autophagy is regulated under these different conditions in plants, but recent evidence suggests that plants contain a functional TOR pathway which may control autophagy induction in conjunction with hormonal and/or environmental signals.

Keywords: Autophagy; Stress; Pathogen; TOR; Arabidopsis; Programmed cell death

Selective types of autophagy in yeast by Claudine Kraft ⁎; Fulvio Reggiori; Matthias Peter ⁎ (pp. 1404-1412).

Autophagy is the process through which cytosol and organelles are sequestered into a double-membrane vesicle called an autophagosome and delivered to the vacuole/lysosome for breakdown and recycling. One of its primary roles in unicellular organisms is to regulate intracellular homeostasis and to adjust organelle numbers in response to stress such as changes in nutrient availability. In higher eukaryotes, autophagy plays also an important role in stress-response, development, cell differentiation, immunity and tumor suppression. Importantly, a misregulation in this catabolic pathway is associated with diseases such as cancer, neurodegeneration and myopathies. For a long time, starvation-induced autophagy has been considered a non-selective pathway, however, numerous recent observations revealed that autophagy can also selectively eliminate specific proteins, protein complexes and organelles. Most of these studies used yeast Saccharomyces cerevisiae as a model organism. In this compendium, we will review what is known about the mechanisms and roles of selective types of autophagy in yeast and highlight possible connections of these pathways with human diseases. In addition, we will discuss some selective types of autophagy, which have so far only been described in higher eukaryotes.

Keywords: Starvation; Autophagy; Cvt pathway; Mitophagy; Pexophagy; Piecemeal autophagy of the nucleus; Reticulophagy; Ribophagy; Aggrephagy; Xenophagy

Regulation of autophagy in yeast Saccharomyces cerevisiae by Eduardo Cebollero; Fulvio Reggiori (pp. 1413-1421).

Autophagy is a conserved catabolic process that initially involves the bulk or the selective engulfment of cytosolic components into double-membrane vesicles and successively the transport of the sequestered cargo material into the lysosome/vacuole for degradation. This pathway allows counteracting internal and external stresses, including changes in the nutrient availability, that alter the cell metabolic equilibrium. Consequently, the regulation of autophagy is crucial for maintaining important cellular functions under various conditions and ultimately it is essential for survival. Yeast Saccharomyces cerevisiae has been successfully employed as a model system to study autophagy. For instance, it has allowed the isolation of the factors specifically involved in autophagy, the Atg proteins, and the characterization of some of their molecular roles. In addition, this organism also possesses all the principal signaling cascades that modulate the cell metabolism in response to nutrient availability in higher eukaryotes, including the TOR and the PKA pathways. Therefore, yeast is an ideal system to study the regulation of autophagy by these signaling pathways. Here, we review the current state of our knowledge about the molecular events leading to the induction or inhibition of autophagy in yeast with special emphasis on the regulation of the function of Atg proteins.

Keywords: Yeast; Autophagy; Cvt pathway; Nutrient; TOR; cAMP/PKA; Sch9/PKB; Filamentous fungi

Autophagic cell death: Analysis in Dictyostelium by Corinne Giusti; Emilie Tresse; Marie-Françoise Luciani; Pierre Golstein (pp. 1422-1431).

Autophagic cell death (ACD) can be operationally described as cell death with an autophagic component. While most molecular bases of this autophagic component are known, in ACD the mechanism of cell death proper is not well defined, in particular because in animal cells there is poor experimental distinction between what triggers autophagy and what triggers ACD. Perhaps as a consequence, it is often thought that in animal cells a little autophagy is protective while a lot is destructive and leads to ACD, thus that the shift from autophagy to ACD is quantitative. The aim of this article is to review current knowledge on ACD in Dictyostelium, a very favorable model, with emphasis on (1) the qualitative, not quantitative nature of the shift from autophagy to ACD, in contrast to the above, and (2) random or targeted mutations of in particular the following genes: iplA (IP3R), TalB (talinB), DcsA (cellulose synthase), GbfA, ugpB, glcS (glycogen synthase) and atg1. These mutations allowed the genetic dissection of ACD features, dissociating in particular vacuolisation from cell death.

Keywords: Abbreviations; ACD; autophagic cell death; NCD; necrotic cell death; DIF-1; differentiation-inducing factor 1; ROS; reactive oxygen speciesAutophagic cell death; Necrotic cell death; Dictyostelium

Autophagy in Hydra: A response to starvation and stress in early animal evolution by Simona Chera; Wanda Buzgariu; Luiza Ghila; Brigitte Galliot ⁎ (pp. 1432-1443).

The Hydra polyp provides a powerful model system to investigate the regulation of cell survival and cell death in homeostasis and regeneration as Hydra survive weeks without feeding and regenerates any missing part after bisection. Induction of autophagy during starvation is the main surviving strategy in Hydra as autophagic vacuoles form in most myoepithelial cells after several days. When the autophagic process is inhibited, animal survival is actually rapidly jeopardized. An appropriate regulation of autophagy is also essential during regeneration as Hydra RNAi knocked-down for the serine protease inhibitor Kazal-type (SPINK) gene Kazal1, exhibit a massive autophagy after amputation that rapidly compromises cell and animal survival. This excessive autophagy phenotype actually mimics that observed in the mammalian pancreas when SPINK genes are mutated, highlighting the paradigmatic value of the Hydra model system for deciphering pathological processes. Interestingly autophagy during starvation predominantly affects ectodermal epithelial cells and lead to cell survival whereas Kazal1(RNAi)-induced autophagy is restricted to endodermal digestive cells that rapidly undergo cell death. This indicates that distinct regulations that remain to be identified, are at work in these two contexts. Cnidarian express orthologs for most components of the autophagy and TOR pathways suggesting evolutionarily-conserved roles during starvation.

Keywords: Hydra; starvation; Hydra; regeneration; Kazal-type serine protease inhibitor; RNA interference; Cnidarian autophagy genes; Evolution

Autophagy in Caenorhabditis elegans by Evgenia V. Megalou; Nektarios Tavernarakis ⁎ (pp. 1444-1451).

Macroautophagy (or autophagy) is a catabolic process responsible for the degradation of long-lived proteins, molecules and organelles. Cellular stressors such as food limitation, space restriction, oxidative stress, temperature shifts, and accumulation of protein aggregates induce autophagy. Cellular material to be degraded is engulfed in autophagosomes, which fuse with the lysosome where material is degraded. Cellular components can then be recycled. Autophagy has been assigned pro-survival and pro-death functions. Here, we reviewed the roles of autophagy in cell growth and death, in ageing and longevity, as well as in neurodegeneration in the nematode Caenorhabditis elegans.

Keywords: Abbreviations; AD; Alzheimer's disease; ALS; amyotrophic lateral sclerosis; Atg; autophagy-related gene; APP; amyloid precursor protein; BH3; Bcl-2 homology region 3; Daf; dauer formation; Deg; degeneration; FOXO; Forkhead box O family of transcription factors; GABA; γ-aminobutyric acid; GFP; green fluorescent protein; HD; Huntington's disease; IGF; insulin-like growth factor; MAPK; mitogen-activated kinase; PD; Parkinson's disease; Pha; pharynx; polyQ; polyglutamine; PTEN; phosphatase and tensin homologue; RNAi; RNA interference; TGF; transforming growth factor; TSCI; tuberous sclerosis complex I; TOR; target of rapamycin; Unc; uncoordinated; UVRAG; UV irradiation resistance-associated geneAgeing; Apoptosis; Autophagy; Caenorhabditis elegans; Cell death; Hypoxia; Longevity; Necrosis; Neurodegeneration

Autophagy in Drosophila melanogaster by Christina K. McPhee; Eric H. Baehrecke ⁎ (pp. 1452-1460).

Macroautophagy (autophagy) is a bulk cytoplasmic degradation process that is conserved from yeast to mammals. Autophagy is an important cellular response to starvation and stress, and plays critical roles in development, cell death, aging, immunity, and cancer. The fruit fly Drosophila melanogaster provides an excellent model system to study autophagy in vivo, in the context of a developing organism. Autophagy ( atg) genes and their regulators are conserved in Drosophila, and autophagy is induced in response to nutrient starvation and hormones during development. In this review we provide an overview of how Drosophila research has contributed to our understanding of the role and regulation of autophagy in cell survival, growth, nutrient utilization, and cell death. Recent Drosophila research has also provided important mechanistic information about the role of autophagy in protein aggregation disorders, neurodegeneration, aging, and innate immunity. Differences in the role of autophagy in specific contexts and/or cell types suggest that there may be cell-context-specific regulators of autophagy, and studies in Drosophila are well-suited to yield discoveries about this specificity.

Keywords: Drosophila; Autophagy; Cell survival; Cell growth; Cell death

Autophagy in cells of the blood by Shida Yousefi; Hans-Uwe Simon (pp. 1461-1464).

Autophagy is a conserved proteolytic mechanism that degrades cytoplasmic material including cell organelles. The importance of autophagy for cell homeostasis and survival has long been appreciated. Recent data suggest that autophagy is also involved in non-metabolic functions that particularly concern blood cells. Here, we review these findings, which point to an important role of autophagy in several cellular functions related to host defense.

Keywords: Autophagy; Antigen presentation; B cell; Dendritic cell; Immunity; Infection; Monocyte; Macrophage; Neutrophil; Phagocytosis; Reticulocyte; T cell

Autophagy in intracellular bacterial infection by Emanuel Campoy; María I. Colombo (pp. 1465-1477).

Numerous pathogens have developed the capacity to invade host cells to be protected from components of the systemic immune system. However, once in the host cells they utilize sophisticated strategies to avoid the powerful machinery built by the cells to kill invading pathogens. In the last few years cumulative evidence indicates that autophagy is one of the most remarkable tools of the intracellular host cell defense machinery that bacteria must confront upon cell invasion. However, several pathogens subvert the autophagic pathway and, manipulate this process at the molecular level, as a strategy to establish a persistent infection. In this review we have summarized the interaction between autophagy and different bacterial pathogens including those that take advantage of the host cell autophagy, allowing successful colonization, as well as those microorganisms which are controlled by autophagy as part of the innate surveillance mechanism.

Keywords: Autophagy; Coxiella burnetii; Mycobacterium tuberculosis; LC3; Legionella pneumophila

Autophagy, antiviral immunity, and viral countermeasures by Sanae Shoji-Kawata; Beth Levine ⁎ (pp. 1478-1484).

The autophagy pathway likely evolved not only to maintain cellular and tissue homeostasis but also to protect cells against microbial attack. This conserved mechanism by which cytoplasmic cargo is delivered to the endolysosomal system is now recognized as a central player in coordinating the host response to diverse intracellular pathogens, including viruses. As an endolysosomal delivery system, autophagy functions in the transfer of viruses from the cytoplasm to the lysosome where they are degraded, in the transfer of viral nucleic acids to endosomal sensors for the activation of innate immunity, and in the transfer of endogenous viral antigens to MHC class II compartments for the activation of adaptive immunity. Viruses have, in turn, evolved different strategies to antagonize, and potentially, to exploit the host autophagic machinery. Moreover, through mechanisms not yet well understood, autophagy may dampen host innate immune and inflammatory responses to viral infection. This review highlights the roles of autophagy in antiviral immunity, viral strategies to evade autophagy, and potential negative feedback functions of autophagy in the host antiviral response.

Keywords: Autophagy; Virus; Immunity

Autophagy in the cardiovascular system by Guido R.Y. De Meyer ⁎; Wim Martinet (pp. 1485-1495).

Autophagy is a catabolic pathway for bulk turnover of long-lived proteins and organelles via lysosomal degradation. Growing evidence reveals that autophagy is involved in the progression or prevention of many human diseases. Here we discuss the role of autophagy in the normal heart, in heart disease and atherosclerosis. In the heart, autophagy functions predominantly as a pro-survival pathway during cellular stress by removing protein aggregates and damaged organelles, protecting the heart against famine, excessive β-adrenergic stimulation and ischemia. However, when severely triggered, e.g. during reperfusion, the autophagic machinery may lead to cell death. Furthermore, autophagy modulates cardiac hypertrophy and the transition from hypertrophy to heart failure. During aging, lipofuscin is formed via autophagy in the heart and impairs autophagy. Basal autophagy in atherosclerotic plaques is a survival mechanism safeguarding plaque cells against cellular distress, in particular oxidative injury, metabolic stress and inflammation, by removing harmful oxidatively modified proteins and damaged components. Hence, autophagy is anti-apoptotic and contributes to cellular recovery in an adverse environment. However, excessively stimulated autophagy causes autophagic death in plaque cells and is detrimental. Ceroid that is formed via autophagy in atherosclerotic arteries impairs autophagy and induces apoptosis. Basal autophagy can be intensified by appropriate drugs and pharmacological approaches have been developed to stabilize rupture-prone plaques through selective induction of macrophage autophagic death, without affecting the plaque stabilizing smooth muscle cells.

Keywords: Atherosclerosis; Autophagy; Cell death; Heart; Heart failure; Ischemia/reperfusion

The cellular pathways of neuronal autophagy and their implication in neurodegenerative diseases by Zhenyu Yue ⁎; Lauren Friedman; Masaaki Komatsu; Keiji Tanaka (pp. 1496-1507).

Autophagy is a tightly regulated cell self-eating process. It has been shown to be associated with various neuropathological conditions and therefore, traditionally known as a stress-induced process. Recent studies, however, reveal that autophagy is constitutively active in healthy neurons. Neurons are highly specialized, post-mitotic cells that are typically composed of a soma (cell body), a dendritic tree, and an axon. Despite the vast growth of our current knowledge of autophagy, the detailed process in such a highly differentiated cell type remains elusive. Current evidence strongly suggests that autophagy is uniquely regulated in neurons and is also highly adapted to local physiology in the axons. In addition, the molecular mechanism for basal autophagy in neurons may be significantly divergent from “classical” induced autophagy. A considerable number of studies have increasingly shown an important role for autophagy in neurodegenerative diseases and have explored autophagy as a potential drug target. Thus, understanding the neuronal autophagy process will ultimately aid in drug target identification and rational design of drug screening to combat neurodegenerative diseases.

Keywords: Autophagy; Neurodegeneration; Neurodegenerative disease; Axon; Axonopathy; Autophagosome; Lysosome; Endosome; Endocytosis; Multiple vesicular bodies (MVB); ESCRT; p62/SQSTM1; Beclin 1; Protein inclusion bodies; Axonal dystrophy; Degeneration

Mitophagy by Aviva M. Tolkovsky (pp. 1508-1515).

Concurrent mitochondrial elimination and autophagy in many systems has led to the proposal that autophagy is the main mechanism of mitochondrial turnover during development and under pathological conditions. The term mitophagy was coined to describe the selective removal of mitochondria by autophagy but the process itself is still contentious. Three questions are being debated: 1) Is there a specific removal of mitochondria by autophagy or is it non-selective or inadvertent? 2) What are the signals that drive this process? 3) Does removal of mitochondria increase or decrease cell viability? There is a mounting evidence for specific signals in/on mitochondria that drive mitochondrial removal from cells by autophagy. The process itself may be both selective and non-selective. In yeast, surprisingly, mitochondrial elimination occurs more by microautophagy (intracellular pinocytosis by the vacuolar membrane) than macroautophagy (initiated by stand-alone nascent double membrane structures known as autophagosomes). In mammalian cells, macroautophagy seems most prevalent though tools to study microautophagy are not well developed. Whilst lack of mitophagy seems to be deleterious, understanding the interplay between autophagy, mitochondrial performance, and cell pathology is a much-needed area of research.

Keywords: Autophagy; Mitochondria; LC3; Parkin; Nix; Ulk1

Role and regulation of autophagy in cancer by Ning Chen; Vassiliki Karantza-Wadsworth (pp. 1516-1523).

Autophagy is an evolutionarily conserved process whereby cytoplasm and cellular organelles are degraded in lysosomes for amino acid and energy recycling. Autophagy is a survival pathway activated in response to nutrient deprivation and other stressful stimuli, such as metabolic stress and exposure to anticancer drugs. However, autophagy may also result in cell death, if it proceeds to completion. Defective autophagy is implicated in tumorigenesis, as the essential autophagy regulator beclin 1 is monoallelically deleted in human breast, ovarian and prostate cancers, andbeclin 1 ^+/− mice are tumor-prone. How autophagy suppresses tumorigenesis is under intense investigation. Cell-autonomous mechanisms, involving protection of genome integrity and stability, and a non-cell-autonomous mechanism, involving suppression of necrosis and inflammation, have been discovered so far. The role of autophagy in treatment responsiveness is also complex. Autophagy inhibition concurrently with chemotherapy or radiotherapy has emerged as a novel approach in cancer treatment, as autophagy-competent tumor cells depend on autophagy for survival under drug- and radiation-induced stress. Alternatively, autophagy stimulation and preservation of cellular fitness by maintenance of protein and organelle quality control, suppression of DNA damage and genomic instability, and limitation of necrosis-associated inflammation may play a critical role in cancer prevention.

Keywords: Autophagy; Tumorigenesis; Tumor suppression; Autophagy regulation; Cancer therapy; Autophagy modulation

Anti- and pro-tumor functions of autophagy by Eugenia Morselli; Lorenzo Galluzzi; Oliver Kepp; José-Miguel Vicencio; Alfredo Criollo; Maria Chiara Maiuri; Guido Kroemer (pp. 1524-1532).

Autophagy constitutes one of the major responses to stress in eukaryotic cells, and is regulated by a complex network of signaling cascades. Not surprisingly, autophagy is implicated in multiple pathological processes, including infection by pathogens, inflammatory bowel disease, neurodegeneration and cancer. Both oncogenesis and tumor survival are influenced by perturbations of the molecular machinery that controls autophagy. Numerous oncoproteins, including phosphatidylinositol 3-kinase, Akt1 and anti-apoptotic members of the Bcl-2 family suppress autophagy. Conversely, several tumor suppressor proteins ( e.g., Atg4c; beclin 1; Bif-1; BH3-only proteins; death-associated protein kinase 1; LKB1/STK11; PTEN; UVRAG) promote the autophagic pathway. This does not entirely apply to p53, one of the most important tumor suppressor proteins, which regulates autophagy in an ambiguous fashion, depending on its subcellular localization. Irrespective of the controversial role of p53, basal levels of autophagy appear to inhibit tumor development. On the contrary, chemotherapy- and metabolic stress-induced activation of the autophagic pathway reportedly contribute to the survival of formed tumors, thereby favoring resistance. In this context, autophagy inhibition would represent a major therapeutic target for chemosensitization. Here, we will review the current knowledge on the dual role of autophagy as an anti- and pro-tumor mechanism.

Keywords: Abbreviations; AMPK; AMP-activated protein kinase; atg; autophagy related; Bec-1; Beclin 1; BH3; Bcl-2 homology domain 3; CRTC; CREB-regulated transcription coactivator; DAPK-1; death-associated protein kinase 1; DRAM; damage-regulated autophagy regulator; LAMP-2; lysosome-associated membrane protein 2; mTOR; mammalian target of rapamycin; NF1; neurofibromin 1; PDPK1; 3-phosphoinositide dependent protein kinase 1; PI3K; phosphatidylinositol 3-kinase; PTEN; phosphatase and tensin homolog; ROS; reactive oxygen species; RTKs; receptor tyrosine kinases; shRNA; short hairpin RNA; siRNA; small interfering RNA; smARF; small mitochondrial ARF; STK11; serine threonine kinase 11; TORC; TOR complex; TRAIL; tumor necrosis factor-related apoptosis inducing ligand; TSC; tuberous sclerosis complex; UPR; unfolded protein response; UVRAG; UV radiation resistance associated gene; WT; wild typeChemosensitization; Oncogene; p53; smARF; Tumor suppressor gene

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BBA - Molecular Cell Research (v.1793, #9)