Calpain-mediated cleavage of Atg5 switches autophagy to apoptosis

Yousefi, Shída; Perozzo, Remo; Schmid, Inès; Ziemiecki, Andrew; Schaffner, Thomas; Scapozza, Léonardo; Brunner, Thomas; Simon, Hans‐Uwe

doi:10.1038/ncb1482

Cited by 1,180 publications

(1,055 citation statements)

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“…21 Our results indicate that ULK1 is one of several ATG proteins that induces cell death through autophagy-independent pathways. 48 They do not exclude the possibility that ULK1 overexpression promotes apoptosis or autophagy-mediated cell death under certain circumstances but rather provide an alternative mechanism for ULK1-dependent cell death that is associated with nuclear localization of ULK1.…”

Section: Discussionmentioning

confidence: 99%

Nuclear ULK1 promotes cell death in response to oxidative stress through PARP1

et al. 2015

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Reactive oxygen species (ROS) may cause cellular damage and oxidative stress-induced cell death. Autophagy, an evolutionarily conserved intracellular catabolic process, is executed by autophagy (ATG) proteins, including the autophagy initiation kinase Unc-51-like kinase (ULK1)/ATG1. Although autophagy has been implicated to have both cytoprotective and cytotoxic roles in the response to ROS, the role of individual ATG proteins, including ULK1, remains poorly characterized. In this study, we demonstrate that ULK1 sensitizes cells to necrotic cell death induced by hydrogen peroxide (H 2 O 2 ). Moreover, we demonstrate that ULK1 localizes to the nucleus and regulates the activity of the DNA damage repair protein poly (ADP-ribose) polymerase 1 (PARP1) in a kinase-dependent manner. By enhancing PARP1 activity, ULK1 contributes to ATP depletion and death of H 2 O 2 -treated cells. Our study provides the first evidence of an autophagy-independent prodeath role for nuclear ULK1 in response to ROS-induced damage. On the basis of our data, we propose that the subcellular distribution of ULK1 has an important role in deciding whether a cell lives or dies on exposure to adverse environmental or intracellular conditions. Cell Death and Differentiation (2016) 23, 216-230; doi:10.1038/cdd.2015; published online 3 July 2015Reactive oxygen species (ROS), such as superoxide and hydrogen peroxide (H 2 O 2 ), are formed by the incomplete reduction of oxygen during oxidative phosphorylation and other enzymatic processes. ROS are signaling molecules that regulate cell proliferation, differentiation, and survival. 1-3 Accumulation of ROS (i.e., oxidative stress) on exposure to xenobiotic agents or environmental toxins can cause cellular damage and death via apoptotic or nonapoptotic pathways. [4][5][6] Oxidative stress-induced cellular damage and death have been implicated in aging, ischemia-reperfusion injury, inflammation, and the pathogenesis of diseases (e.g., neurodegeneration and cancer). 7 Oxidative stress also contributes to the antitumor effects of many chemotherapeutic drugs, including camptothecin 8,9 and selenite. 10,11 Autophagy, an evolutionarily conserved intracellular catabolic process, involves lysosome-dependent degradation of superfluous and damaged cytosolic organelles and proteins. 12 It is typically upregulated under conditions of perceived stress and in response to cellular damage. The consequence of autophagy activation -whether cytoprotective or cytotoxicappears to depend on the cell type and the nature and extent of stress. Although most studies indicate a cytoprotective role for autophagy, some evidence suggests that it contributes to cell death in response to oxidative stress. [13][14][15][16][17] Studies have also indicated that autophagy may be suppressed in response to oxidative stress, thereby sensitizing certain cells to apoptosis. 18,19 Unc-51-like kinase/autophagy 1 (ULK1/ATG1) is a mammalian serine-threonine kinase that regulates flux through the autophagy pathway by activating the VPS34 PI(3) kinas...

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Section: Discussionmentioning

confidence: 99%

Nuclear ULK1 promotes cell death in response to oxidative stress through PARP1

et al. 2015

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“…Examples for the induction of apoptosis with the help of autophagy regulators, such as the p53-induced dram and the calpain-generated cleavage product of atg5, have been described. 29,30 It is also possible that elements of the apoptosis machinery, while killing cells, may initiate autophagy to fasten self-elimination even before phagocytosis; in our case loss of integrin-dependent survival pathways may lead to induction of death effectors' which in turn converge onto mediators of autophagy, such as Atg5, Atg7 and beclin-1. Nevertheless, inhibition of autophagy by 3-MA in these anoikic-autophagic cells have resulted in less inhibition of cell death than in de novo autophagic cells and, most importantly, did not have an effect on the engulfment of these anoikic-autophagic cells by either of the phagocytic cell types.…”

Section: Discussionmentioning

confidence: 99%

Clearance of dying autophagic cells of different origin by professional and non-professional phagocytes

et al. 2007

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MCF-7 cells undergo autophagic death upon tamoxifen treatment. Plated on non-adhesive substratum these cells died by anoikis while inducing autophagy as revealed by monodansylcadaverine staining, elevated light-chain-3 expression and electron microscopy. Both de novo and anoikis-derived autophagic dying cells were engulfed by human macrophages and MCF-7 cells. Inhibition of autophagy by 3-methyladenine abolished engulfment of cells dying through de novo autophagy, but not those dying through anoikis. Blocking exposure of phosphatidylserine (PS) on both dying cell types inhibited phagocytosis by MCF-7 but not by macrophages. Gene expression profiling showed that though both types of phagocytes expressed full repertoire of the PS recognition and signaling pathway, macrophages could evolve during engulfment of de novo autophagic cells the potential of calreticulin-mediated processes as well. Our data suggest that cells dying through autophagy and those committing anoikis with autophagy may engage in overlapping but distinct sets of clearance mechanisms in professional and non-professional phagocytes.

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“…The implication of these studies is that Atg5 can regulate components of the extrinsic apoptosis pathway. Another mechanism by which Atg5 can regulate apoptosis has also been described (79). The key step in this mechanism is the cleavage of Atg5 by calpain to create a truncated form of the protein that translocates to the mitochondria to cause cytochrome c release and activation of the intrinsic apoptosis pathway that can be blocked by Bcl-2.…”

Section: Molecular Connections Between Autophagy and Apoptosismentioning

confidence: 99%

“…The general significance of this mechanism is suggested by data showing that Atg5 knockdown protects tumor cells towards a variety of apoptosis stimuli while Atg5 expression sensitized to these apoptotic stimuli. Again the situation may be rather complex and calpain activity may both increase and decrease autophagy because while calpain cleavage of Atg5 produces a protein that cannot activate autophagy (79), other studies show that calpain activity is required for autophagy induction by rapamycin and amino acid starvation (80). Further discussion of interactions between apoptosis and autophagy can also be found in a recent review article by Maiuri et.al.…”

Section: Molecular Connections Between Autophagy and Apoptosismentioning

confidence: 99%

Apoptosis and autophagy: regulatory connections between two supposedly different processes

2007

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Apoptosis and autophagy are genetically-regulated, evolutionarily-conserved processes that regulate cell fate. Both apoptosis and autophagy are important in development and normal physiology and in a wide range of diseases. Recent studies show that despite the marked differences between these two processes, their regulation is intimately connected and the same regulators can sometimes control both apoptosis and autophagy. In this review, I discuss some of these findings, which provide possible molecular mechanisms for crosstalk between apoptosis and autophagy and suggest that it may be useful to think of these processes as different facets of the same cell death continuum rather than completely separate processes. KeywordsAutophagy; Apoptosis; Bcl-2, FADD; Atg 5In the early to mid 1990s there was a rapid increase in our understating about the regulation of apoptosis. Fifteen or so years later we are in the midst of a similarly exciting period for understanding autophagy with very rapid growth of publications on the regulation and function of this process (1). Autophagy (the form of autophagy discussed here is macroautophagy, other forms-microautophagy and chaperone-mediated autophagy share the same lysosomal degradation mechanism but differ in the way that material is delivered to the lysosome) is a degradative process involving sequestration of parts of the cytoplasm in double membrane vesicles (autophagic vesicles or autophagosomes) that fuse with lysosomes forming the autophagolysosome. In the autophagolysosome, the cytoplasmic material that was engulfed is hydrolyzed and the resulting amino acids and other macromolecular precursors can be recycled (2-4), see Fig 1 for a schematic of the process. Autophagy is a mechanism by which organelles are removed and is the primary degradation mechanism for long-lived proteins and thus maintains quality control for proteins and organelles. Autophagy is ubiquitous in eukaryotic cells and important in development and in diverse pathophysiological conditions (5)-for example providing protection against neurodegeneration (6,7), infections (8,9) and tumor development (10-13). Cells that are deficient in autophagy also demonstrate enhanced chromosomal instability (14,15), which may be related to the tumorigenesis associated with autophagy deficiency.Autophagy is important in cell death decisions and can protect cells by preventing them from undergoing apoptosis. For example, increased autophagy in nutrient deprived or growth factorwithdrawn cells allows cell survival (16,17) by inhibiting apoptosis. Autophagy also protects cells from various other apoptotic stimuli (18). It is not clear how autophagy stops cells from undergoing apoptosis; one suggested mechanism is the sequestration of damaged mitochondria (18) thus preventing released cytochrome c from being able to form a functional apoptosome NIH Public Access Autophagic cell death (also known as Type II programmed cell death to distinguish it from apoptosis or Type I programmed cell death) (20-22) has been describ...

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Calpain-mediated cleavage of Atg5 switches autophagy to apoptosis

Cited by 1,180 publications

References 36 publications

Nuclear ULK1 promotes cell death in response to oxidative stress through PARP1

Nuclear ULK1 promotes cell death in response to oxidative stress through PARP1

Clearance of dying autophagic cells of different origin by professional and non-professional phagocytes

Apoptosis and autophagy: regulatory connections between two supposedly different processes

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