The stressosome,a caspase-8-activating signalling complex assembled in response to cell stress in an ATG5-mediated manner |
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Authors: | Katarzyna Mnich Izabela Koryga Karolina Pakos-Zebrucka Melissa Thomas Susan E Logue Leif A Eriksson Adrienne M Gorman Afshin Samali |
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Institution: | 1. Apoptosis Research Centre, NUI Galway, Galway, Ireland;2. Apoptosis Research Centre, NUI Galway, Galway, Ireland
School of Natural Sciences, NUI Galway, Galway, Ireland
CÚRAM SFI Research Centre for Medical Devices, NUI Galway, Galway, Ireland
Contribution: Formal analysis (equal), ?Investigation (equal), Methodology (equal);3. Department of Chemistry and Molecular Biology, University of Gothenburg, Göteborg, Sweden |
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Abstract: | Stress-induced apoptosis is mediated primarily through the intrinsic pathway that involves caspase-9. We previously reported that in caspase-9-deficient cells, a protein complex containing ATG5 and Fas-associated death domain (FADD) facilitated caspase-8 activation and cell death in response to endoplasmic reticulum (ER) stress. Here, we investigated whether this complex could be activated by other forms of cell stress. We show that diverse stress stimuli, including etoposide, brefeldin A and paclitaxel, as well as heat stress and gamma-irradiation, caused formation of a complex containing ATG5-ATG12, FADD and caspase-8 leading to activation of downstream caspases in caspase-9-deficient cells. We termed this complex the ‘stressosome’. However, in these cells, only ER stress and heat shock led to stressosome-dependent cell death. Using in silico molecular modelling, we propose the structure of the stressosome complex, with FADD acting as an adaptor protein, interacting with pro-caspase-8 through their respective death effector domains (DEDs) and interacting with ATG5-ATG12 through its death domain (DD). This suggests that the complex could be regulated by cellular FADD-like interleukin-1β-converting enzyme–inhibitory protein (cFLIPL), which was confirmed experimentally. This study provides strong evidence for an alternative mechanism of caspase-8 activation involving the stressosome complex. |
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Keywords: | apoptosis autophagy caspase cell stress integrated stress response |
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