The stressosome, a caspase‐8‐activating signalling complex assembled in response to cell stress in an ATG5‐mediated manner

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.

Chamaecyparis lawsoniana Leaf Essential Oil as a Potential Anticancer Agent: Experimental and Computational Studies

“…On the other hand, caspase-8 is one of cysteine proteases involved in the induction of extrinsic apoptosis where it acts as initiator for the apoptosis signal propagation via direct cleavage of downstream effector caspases such as caspase-3. Furthermore, it has a vital role in several cellular processes included in cancer development and progression [65,66]. Consequently, Mcl-1 and Caspase-8 constitute appealing molecular targets for the development of new anticancer drugs.…”

A novel BH3 mimetic Bcl-2 inhibitor promotes autophagic cell death and reduces in vivo Glioblastoma tumor growth

“…BAU-243 treatment upregulated gene expression levels of BECN1 , as well as other autophagy-related genes such as ATG5 , and MAP1LC3B . Atg5 plays an important role in initial autophagosome formation, moreover, it acts as an inter-player between autophagy and apoptosis [ 18 , 45 , 46 ]. Both upregulated gene expression levels and abundant Lc3b expression in cells shown by western blots and immunocytochemistry upon BAU-243 treatment indicate that autophagy is induced through BAU-243 treatment.…”

The Role of Cytokines in Cholesterol Accumulation in Cells and Atherosclerosis Progression

“…To initiate apoptosis, TRADD binds to a second adaptor protein called Fas-associated protein with death domain (FADD) causing caspase-8/10 activation, triggering a series of caspase cleavages that culminate in cellular apoptosis. The FADD complex in combination with procaspase-8/10 is called the death-inducing signaling complex (DISC) [ 57 , 58 , 59 , 60 ].…”