Article ; Online: The stressosome, a caspase-8-activating signalling complex assembled in response to cell stress in an ATG5-mediated manner.
Journal of cellular and molecular medicine
2021 Volume 25, Issue 18, Page(s) 8809–8820
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 ...
| 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 (cFLIP |
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| MeSH term(s) | Animals ; Autophagy-Related Protein 5/metabolism ; Caspase 8/metabolism ; Caspase 9/metabolism ; Endoplasmic Reticulum Stress ; Fibroblasts ; HEK293 Cells ; Humans ; Mice ; Mouse Embryonic Stem Cells |
| Chemical Substances | ATG5 protein, human ; Autophagy-Related Protein 5 ; CASP8 protein, human (EC 3.4.22.-) ; CASP9 protein, human (EC 3.4.22.-) ; Caspase 8 (EC 3.4.22.-) ; Caspase 9 (EC 3.4.22.-) |
| Language | English |
| Publishing date | 2021-08-07 |
| Publishing country | England |
| Document type | Journal Article ; Research Support, Non-U.S. Gov't |
| ZDB-ID | 2074559-X |
| ISSN | 1582-4934 ; 1582-4934 ; 1582-1838 |
| ISSN (online) | 1582-4934 |
| ISSN | 1582-4934 ; 1582-1838 |
| DOI | 10.1111/jcmm.16840 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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