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

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

Author(s): 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;
Details: Publication Year 2023-07-28,Volume 9,Issue #30,Page eadg2829
Journal Title: Science Advances
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.
Research Division(s): Blood Cells And Blood Cancer
Publisher's Version: https://doi.org/10.1126/sciadv.adg2829
Open Access at Publisher's Site: https://doi.org/10.1126/sciadv.adg2829
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2023-08-04 12:44:16

Last Modified: 2023-08-04 01:39:29