Role of JNK1-dependent Bcl-2 Phosphorylation in Ceramide-induced Macroautophagy

Pattingre, Sophie; Bauvy, Chantal; Carpentier, Stéphane; Levade, Thierry; Levine, Beth; Codogno, Patrice

doi:10.1074/jbc.m805920200

Cited by 248 publications

(220 citation statements)

References 81 publications

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“…37 A recent report suggested that phosphorylation of the antiapoptotic protein BCL-2 at the ER membrane by JNK, possibly by ceramide elevation, may directly affect the initiation of autophagy by modulating the activity of Beclin-1. 39 Activation of eIF2a by PERK causes the induction of Atg12 expression by ATF4, which likely participates in autophagy. 17 In this regard, PERK has been shown to activate Akt as a mechanism to protect cells from ER stress-induced apoptosis.…”

Section: Discussionmentioning

confidence: 99%

Sphingosine-1-phosphate phosphohydrolase-1 regulates ER stress-induced autophagy

et al. 2010

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The sphingolipid metabolites ceramide and sphingosine-1-phosphate (S1P) have recently been implicated in autophagy. In this study, we report that depletion of sphingosine-1-phosphate phosphohydrolase-1 (SPP1), an endoplasmic reticulum (ER)-resident enzyme that specifically dephosphorylates S1P, induced autophagy. Although the mammalian target of rapamycin and class III phosphoinositide 3-kinase/Beclin-1 pathways were not involved and this autophagy was p53 independent, C/EBP homologous protein, BiP, and phospho-eucaryotic translation initiation factor-2a, and cleavage of procaspases 2 and 4, downstream targets of ER stress, were increased after SPP1 depletion. Autophagy was suppressed by depletion of protein kinase regulated by RNA-like ER kinase (PERK), inositol-requiring transmembrane kinase/endonuclease-1a, or activating transcription factor 6, three sensors of the unfolded protein response (UPR) to ER stress. Autophagy triggered by downregulation of SPP1 did not lead to apoptosis but rather stimulated, in a PERK dependent manner, the survival signal Akt, whose inhibition then sensitized cells to apoptosis. Although depletion of SPP1 increased intracellular levels of S1P and its secretion, activation of cell surface S1P receptors did not induce autophagy. Nevertheless, increases in intracellular pools of S1P, but not dihydro-S1P, induced autophagy and ER stress. Thus, SPP1, by regulating intracellular S1P homeostasis, can control the UPR and ER stress-induced autophagy.

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Section: Discussionmentioning

confidence: 99%

Sphingosine-1-phosphate phosphohydrolase-1 regulates ER stress-induced autophagy

et al. 2010

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“…Autophagy has been shown to be necessary for apoptotic cell death, placing it upstream of apoptosis, whereas simultaneously modulating an independent means of death (2). Or, apoptosis may suppress autophagy, so that the latter is only evident on inhibition of apoptosis (3). (b) Autophagy antagonizes apoptotic cell death by promoting cell survival, through, for example, the removal of damaged organelles that are a source of genotoxic ROS, or by catabolizing cellular macromolecules to provide a source of nutrients and energy for the starved cell, or by limiting ER stress through the degradation of unfolded protein aggregates.…”

Section: Conceptual Cross-talkmentioning

confidence: 99%

“…(c) Autophagy, although not leading to cell death by itself, enables the apoptotic program by participating in certain morphological changes, such as ATP-dependent events such as PS exposure and membrane blebbing Numerous studies showing the cooperative relationship between apoptosis and autophagy exist in the literature. Several commonly known inducers of apoptosis have been shown to also activate autophagy, such as etoposide in mouse embryonic fibroblasts (MEFs), 2 ceramide in breast and colon carcinoma 3 and activation of the TRAIL receptor-2 in cancer cells. 4 Furthermore, the simultaneous activation of both pathways has been observed in experimental settings and in clinical trials.…”

Section: Conceptual Cross-talkmentioning

confidence: 99%

“…53 In the reciprocal manner, JNK phosphorylates Bcl-2, triggering its release from Beclin 1, 54 following starvation or ceramideinduced autophagy. 3,54 A second mechanism leading to dissociation of the complex involves the competitive displacement of Beclin 1's BH3 domain from Bcl-2/Bcl-X L by other BH3-containing proteins, 50 such as BNIP3. 55 BNIP3 is a BH3-only member of the Bcl-2 family that is upregulated by hypoxia and previously reported to play a role in apoptosis.…”

Section: Molecular Cross-talkmentioning

confidence: 99%

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Life and death partners: apoptosis, autophagy and the cross-talk between them

et al. 2009

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It is not surprising that the demise of a cell is a complex well-controlled process. Apoptosis, the first genetically programmed death process identified, has been extensively studied and its contribution to the pathogenesis of disease well documented. Yet, apoptosis does not function alone to determine a cell's fate. More recently, autophagy, a process in which de novo-formed membrane-enclosed vesicles engulf and consume cellular components, has been shown to engage in a complex interplay with apoptosis. In some cellular settings, it can serve as a cell survival pathway, suppressing apoptosis, and in others, it can lead to death itself, either in collaboration with apoptosis or as a back-up mechanism when the former is defective. The molecular regulators of both pathways are inter-connected; numerous death stimuli are capable of activating either pathway, and both pathways share several genes that are critical for their respective execution. The cross-talk between apoptosis and autophagy is therefore quite complex, and sometimes contradictory, but surely critical to the overall fate of the cell. Furthermore, the crosstalk is a key factor in the outcome of death-related pathologies such as cancer, its development and treatment. Autophagy, a process long known to provide a survival advantage to cells undergoing nutrient deprivation or other stresses, has also been more recently linked to the actual death process itself. Thus apoptosis is not the sole means by which the cell can undergo a genetically programmed regulated process by which it undergoes self-elimination. Cell death can occur by several mechanisms and the phenotypic changes that accompany cell death can vary depending on the stimulus and cell setting. In any given death scenario, the cell decides which pathway to use, depending on the nature of the stimulus and the particulars of the cell environment. Furthermore, apoptosis and autophagy are not mutually exclusive pathways. They have been shown to act in synergy and also to counter each other. They share many of the same molecular regulators. In a clinical setting, one cannot predict the outcome of inhibition or activation of one death program without considering the effect on the other. This review will focus on the cross-talk between the autophagic and apoptotic pathways, with an analysis of how this may affect the clinical applications of death suppression/activation to cancer. The process of necrosis, the third means by which the cell can undergo a genetically programmed self-elimination, will not be discussed in detail. Although not intended to provide an exhaustive summary of the recent literature, the discussion will include salient experimental results as examples of the different facets of the apoptosis/autophagy interplay.An issue that has been raised and discussed in the literature is that in many cell settings, autophagy accompanies, rather than causes, cell death. 1 This argument is based on the fact that many studies that claim autophagic cell death prove that autophagy occurs, and that ...

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“…The constitutive Bcl-2/Bcl-X L :Beclin 1 interaction is disrupted by signals that promote autophagy. Importantly, c-Jun N-terminal kinase 1 (JNK-1) phosphorylates three amino acids in the N-terminal loop of Bcl-2 to trigger its release from Beclin 1 [117] in response to starvation or ceramide treatment [117,118]. In a reciprocal manner, the BH3 domain of Beclin 1 can be phosphorylated by death-associated protein kinase (DAPK), which has the effect of reducing its affinity for Bcl-X L [119].…”

Section: Cytoplasmic Regulation Mtorc1 and Mtorc2mentioning

confidence: 99%

Overview of macroautophagy regulation in mammalian cells

et al. 2010

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Macroautophagy is a multistep, vacuolar, degradation pathway terminating in the lysosomal compartment, and it is of fundamental importance in tissue homeostasis. In this review, we consider macroautophagy in the light of recent advances in our understanding of the formation of autophagosomes, which are double-membrane-bound vacuoles that sequester cytoplasmic cargos and deliver them to lysosomes. In most cases, this final step is preceded by a maturation step during which autophagosomes interact with the endocytic pathway. The discovery of AuTophaGyrelated genes has greatly increased our knowledge about the mechanism responsible for autophagosome formation, and there has also been progress in the understanding of molecular aspects of autophagosome maturation. Finally, the regulation of autophagy is now better understood because of the discovery that the activity of Atg complexes is targeted by protein kinases, and owing to the importance of nuclear regulation via transcription factors in regulating the expression of autophagy genes.

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Role of JNK1-dependent Bcl-2 Phosphorylation in Ceramide-induced Macroautophagy

Cited by 248 publications

References 81 publications

Sphingosine-1-phosphate phosphohydrolase-1 regulates ER stress-induced autophagy

Sphingosine-1-phosphate phosphohydrolase-1 regulates ER stress-induced autophagy

Life and death partners: apoptosis, autophagy and the cross-talk between them

Overview of macroautophagy regulation in mammalian cells

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