Cleavage of cFLIP restrains cell death during viral infection and tissue injury and favors tissue repair.
Date
2023-07-28ICR Author
Author
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
Type
Journal Article
Metadata
Show full item recordAbstract
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.
Collections
Subject
Animals
Mice
Caspase 8
Apoptosis
Skin
Tumor Necrosis Factor-alpha
Virus Diseases
Research team
Cell Death and Immunity
Language
eng
Date accepted
2023-06-22
License start date
2023-07-28
Citation
Science Advances, 2023, 9 (30), pp. eadg2829 -
Publisher
AMER ASSOC ADVANCEMENT SCIENCE