Autophagy is required for necrotic cell death in Caenorhabditis elegans

Samara, Chrysanthi; Syntichaki, Popi; Tavernarakis, Nektarios

doi:10.1038/sj.cdd.4402231

Cited by 169 publications

(164 citation statements)

References 40 publications

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“…Moreover, Beclin-1 is bound to many other proteins in addition to Bcl-2 family members (Vps34 (Furuya et al, 2005), UVRAG (Liang et al, 2006;Takahashi et al, 2007), Bif1 (Takahashi et al, 2007) Ambra (Fimia et al, 2007)), which may further obscure the function of the BH3-domain. It is interesting to note that UVRAG was recently reported to modulate the stoichiometry of Beclin-1 binding to Bcl-2/xL (Noble et al, 2008;Samara et al, 2008), but the impact on apoptosis is not known. Our studies with Vps34 did not reveal a difference in the amount of Vps34 that coimmunoprecipitates or colocalizes with Beclin-1 in the absence or presence of Bcl-2 (CL Tan and I Ciechomska, unpublished data), in keeping with the data of Maiuri et al (2007a), but not that of Pattingre et al (2005).…”

Section: Discussionmentioning

confidence: 99%

“…In cancer cells, autophagy inhibited starvation-induced apoptotic death (Boya et al, 2005) and also necrotic cell death, especially in conjunction with a block in apoptosis (Jin and White, 2007;Karantza-Wadsworth et al, 2007). Conversely, autophagy was required for necrotic death of neuronal cells in C. elegans (Samara et al, 2008), for stress-mediated necrosis in apoptosis-deficient BaxÀ/ÀBakÀ/À mouse embryonic fibroblasts (MEFs) (Shimizu et al, 2004;Ullman et al, 2008) and loss of autophagy through deletion of Atg7 rescued neurons from death after hypoxia/reperfusion (Koike et al, 2008). Resolving the relationship between autophagy and apoptosis is especially complex, as both are induced by similar stimuli and impact on each other's functions (Maiuri et al, 2007c;Levine et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

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Bcl-2 complexed with Beclin-1 maintains full anti-apoptotic function

et al. 2009

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The binding of Bcl-2 to Beclin-1 reduces Beclin-1's capacity to induce autophagy. Here, we have tested whether the interaction is reciprocated by loss of Bcl-2's anti-apoptotic function. We targeted Bcl-2 to mitochondria or endoplasmic reticulum (ER) and induced apoptosis using several apoptotic stimuli that initiate ER and/or mitochondrial signaling pathways (UV radiation, TNF and cycloheximide, staurosporine, thapsigargin and tunicamycin). When Beclin-1 and Bcl-2 were expressed together in HeLa cells, Beclin-1 (but not Beclin-1 lacking the Bcl-2-binding domain) followed Bcl-2 to the appropriate organelle with complete or near-complete overlap (comprising 60 and 30% of cells, respectively). The interaction between Beclin-1 and Bcl-2 was verified by immunoprecipitation, and a membrane-proximate localization of Beclin-1 was shown by immunoelectron microscopy. Apoptosis was followed by measuring changes in nuclear morphology, caspase-3 activity, poly-ADP-ribose polymerase cleavage or punctation of mRFP-Bax on mitochondria. Binding of Beclin-1 to Bcl-2 did not modify apoptosis irrespective of Bcl-2 concentration, location or apoptotic stimulus. A similar result was obtained in Atg5À/À cells that are autophagy-deficient, arguing against compensation for the loss of protection by Bcl-2 by autophagy-mediated survival induced by Beclin-1. Hence, although Beclin-1 contains a BH3-only motif typical of pro-apoptotic proteins, it is a negligible modulator of Bcl-2's anti-apoptotic function.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Bcl-2 complexed with Beclin-1 maintains full anti-apoptotic function

et al. 2009

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“…Indeed, there are no or few convincing examples in which specific inhibition of autophagy by knockout or knockdown of essential autophagy-relevant genes (the ATG gene) would fully inhibit cell death induced by specific stressors or pharmacological agents (Shimizu et al, 2004(Shimizu et al, , 2010Berry and Baehrecke, 2007;Samara et al, 2008;Turcotte et al, 2008). Rather, autophagy is usually a self-limited process that protects cells from death by multiple mechanisms, including improved maintenance of bioenergetic homeostasis, recycling of misfolded and aggregate prone proteins, and removal of damaged organelles such as uncoupled or permeabilized mitochondria Mizushima et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

Association and dissociation of autophagy, apoptosis and necrosis by systematic chemical study

et al. 2011

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To address the question of whether established or experimental anticancer chemotherapeutics can exert their cytotoxic effects by autophagy, we performed a highcontent screen on a set of cytotoxic agents. We simultaneously determined parameters of autophagy, apoptosis and necrosis on cells exposed to B1400 compounds. Many agents induced a 'pure' autophagic, apoptotic or necrotic phenotype, whereas less than 100 simultaneously induced autophagy, apoptosis and necrosis. A systematic analysis of the autophagic flux induced by the most potent 80 inducers of GFP-LC3 puncta among the NCI panel agents showed that 59 among them truly induced autophagy. The remaining 21 compounds were potent inducers of apoptosis or necrosis, yet failed to stimulate an autophagic flux, which were characterized as microtubule inhibitors. Knockdown of ATG7 was efficient in preventing GFP-LC3 puncta, yet failed to attenuate cell death by the agents that induce GFP-LC3 puncta. Thus there is not a single compound that would induce cell death by autophagy in our screening, underscoring the idea that cell death is rarely, if ever, executed by autophagy in human cells.

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“…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) kinase complex and facilitating ATG9-dependent membrane recycling.…”

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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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Autophagy is required for necrotic cell death in Caenorhabditis elegans

Cited by 169 publications

References 40 publications

Bcl-2 complexed with Beclin-1 maintains full anti-apoptotic function

Bcl-2 complexed with Beclin-1 maintains full anti-apoptotic function

Association and dissociation of autophagy, apoptosis and necrosis by systematic chemical study

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

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