Deficiency in the mitochondrial apoptotic pathway reveals the toxic potential of autophagy under ER stress conditions
| Autor: | Sanjeev Gupta, Karolina Pakos-Zebrucka, Peter Vandenabeele, Susan E. Logue, Mathieu J.M. Bertrand, Afshin Samali, Svetlana Saveljeva, Shane Deegan |
|---|---|
| Rok vydání: | 2014 |
| Předmět: |
endoplasmic-reticulum stress
Fas-Associated Death Domain Protein GAPDH glyceraldehyde 3-phosphate dehydrogenase ATG autophagy related chain DDIT3 DNA-damage-inducible transcript 3 Endoplasmic Reticulum Autophagy-Related Protein 7 caspase-8 Autophagy-Related Protein 5 cytochrome-c FADD Fas (TNFRSF6)-associated via death domain Mice 0302 clinical medicine HSPA5 heat shock 70 kDa protein 5 (glucose-regulated protein 78 kDa) MOMP mitochondrial outer membrane permeabilization FADD Endoplasmic Reticulum Chaperone BiP Caspase TNF tumor necrosis factor Caspase 8 0303 health sciences biology Caspase 3 MEFs mouse embryonic fibroblasts BCL2 B-cell CLL/lymphoma 2 apoptosis BAK1 BCL2-antagonist/killer 1 unfolded protein response Caspase 9 Mitochondria Cell biology BAX BCL2-associated X protein autophagic cell death 030220 oncology & carcinogenesis endoplasmic reticulum stress Tm tunicamycin roles Microtubule-Associated Proteins PARP poly (ADP-ribose) polymerase Signal Transduction DISC death inducing signaling complex autophagy Programmed cell death Basic Research Papers assays caspase fadd ATG5 PBS phosphate-buffered saline ER endoplasmic reticulum PI propidium iodide 03 medical and health sciences Animals Humans Molecular Biology 030304 developmental biology Bcl-2 family Cell Biology Fibroblasts cell-death Enzyme Activation MAP1LC3 (LC3) microtubule-associated protein 1 light chain 3 HEK293 Cells Gene Expression Regulation DTT dithiothreitol TNFSF10 tumor necrosis factor (ligand) superfamily member 10 Tg thapsigargin biology.protein activation bcl-2 family |
| Zdroj: | Autophagy |
| ISSN: | 1554-8635 1554-8627 |
| Popis: | Endoplasmic reticulum (ER) stress-induced cell death is normally associated with activation of the mitochondrial apoptotic pathway, which is characterized by CYCS (cytochrome c, somatic) release, apoptosome formation, and caspase activation, resulting in cell death. In this study, we demonstrate that under conditions of ER stress cells devoid of CASP9/caspase-9 or BAX and BAK1, and therefore defective in the mitochondrial apoptotic pathway, still undergo a delayed form of cell death associated with the activation of caspases, therefore revealing the existence of an alternative stress-induced caspase activation pathway. We identified CASP8/caspase-8 as the apical protease in this caspase cascade, and found that knockdown of either of the key autophagic genes, ATG5 or ATG7, impacted on CASP8 activation and cell death induction, highlighting the crucial role of autophagy in the activation of this novel ER stress-induced death pathway. In line with this, we identified a protein complex composed of ATG5, FADD, and pro-CASP8 whose assembly coincides with caspase activation and cell death induction. Together, our results reveal the toxic potential of autophagy in cells undergoing ER stress that are defective in the mitochondrial apoptotic pathway, and suggest a model in which the autophagosome functions as a platform facilitating pro-CASP8 activation. Chemoresistance, a common problem in the treatment of cancer, is frequently caused by the downregulation of key mitochondrial death effector proteins. Alternate stress-induced apoptotic pathways, such as the one described here, may become of particular relevance for tackling the problem of chemoresistance in cancer cells. |
| Databáze: | OpenAIRE |
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