Cleavage of cFLIP restrains cell death during viral infection and tissue injury and favors tissue repair.
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ICR Authors
Authors
Martinez Lagunas, K
Savcigil, DP
Zrilic, M
Carvajal Fraile, C
Craxton, A
Self, E
Uranga-Murillo, I
de Miguel, D
Arias, M
Willenborg, S
Piekarek, M
Albert, MC
Nugraha, K
Lisewski, I
Janakova, E
Igual, N
Tonnus, W
Hildebrandt, X
Ibrahim, M
Ballegeer, M
Saelens, X
Kueh, A
Meier, P
Linkermann, A
Pardo, J
Eming, S
Walczak, H
MacFarlane, M
Peltzer, N
Annibaldi, A
Savcigil, DP
Zrilic, M
Carvajal Fraile, C
Craxton, A
Self, E
Uranga-Murillo, I
de Miguel, D
Arias, M
Willenborg, S
Piekarek, M
Albert, MC
Nugraha, K
Lisewski, I
Janakova, E
Igual, N
Tonnus, W
Hildebrandt, X
Ibrahim, M
Ballegeer, M
Saelens, X
Kueh, A
Meier, P
Linkermann, A
Pardo, J
Eming, S
Walczak, H
MacFarlane, M
Peltzer, N
Annibaldi, A
Document Type
Journal Article
Date
2023-07-28
Date Accepted
2023-06-22
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, CflipD377A, 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.
Citation
Science Advances, 2023, 9 (30), pp. eadg2829 -
Source Title
Science Advances
Publisher
AMER ASSOC ADVANCEMENT SCIENCE
ISSN
2375-2548
eISSN
2375-2548
2375-2548
2375-2548
Collections
Research Team
Cell Death and Immunity