Cleavage of cFLIP restrains cell death during viral infection and tissue injury and favors tissue repair

Abstract

Cell death coordinates repair programs following pathogen attack and tissue injury. However, aberrant cell death can interfere with such programs and cause organ failure. Cellular FLICE-like inhibitory protein (cFLIP) is a crucial regulator of cell death and a substrate of Caspase-8. However, the physiological role of cFLIP cleavage by Caspase-8 remains elusive. Here, we found an essential role for cFLIP cleavage in restraining cell death in different pathophysiological scenarios. Mice expressing a cleavage-resistant cFLIP mutant, Cflip D377A , exhibited increased sensitivity to severe acute respiratory syndrome coronavirus (SARS-CoV)–induced lethality, impaired skin wound healing, and increased tissue damage caused by Sharpin deficiency. In vitro, abrogation of cFLIP cleavage sensitizes cells to tumor necrosis factor(TNF)–induced necroptosis and apoptosis by favoring complex-II formation. Mechanistically, the cell death–sensitizing effect of the D377A mutation depends on glutamine-469. These results reveal a crucial role for cFLIP cleavage in controlling the amplitude of cell death responses occurring upon tissue stress to ensure the execution of repair programs.

Cell death as an architect of adult skin stem cell niches

“…While apoptosis is paramount for skin regeneration, it is clear that proper control of apoptotic cell death rates determines the healing kinetics. This is also exemplified in a mouse model in which the crucial cell death regulator cFLIP can no longer be cleaved by caspase-8, resulting in exaggerated cell death and a significant delay in skin regeneration [138]. Not only do extrinsic apoptotic pathways mediate skin regeneration, but the deregulation of intrinsic apoptotic signalling in HFSCs can accelerate cutaneous wound responses [139].…”

RIPK3 cleavage is dispensable for necroptosis inhibition but restricts NLRP3 inflammasome activation

“…Mice expressing CYLD D215A develop normally, suggesting that cleavage of CYLD at D215 is not essential to repress necroptosis [25]. cFLIP, another caspase-8 substrate that regulates necroptosis, did not undergo lethal necroptosis when its cleavage was genetically blocked in mice [25,26]. Furthermore, we and others have shown that rather than just inhibiting necroptosis, caspase-8-mediated RIPK1 cleavage is a mechanism to dissociate complex II/RIPoptosome to block apoptosis and autoinflammation [25,[27][28][29][30].…”

RIPK1 is dispensable for cell death regulation in β-cells during hyperglycemia

“…cFLIP ( CFLAR ) is a direct substrate and regulator of Caspase-8. It regulates levels of apoptosis by restraining the full activation of Caspase-8 [ 4 ]. Yet, the cFLIP/Caspase-8 heterodimer still bears sufficient activity to prevent another type of cell death called necroptosis [ 5 ].…”