Lagunas, Kristel Martinez;
Savcigil, Deniz Pinar;
Zrilic, Matea;
Fraile, Carlos Carvajal;
Craxton, Andrew;
Self, Emily;
Uranga-Murillo, Iratxe;
... Annibaldi, Alessandro; + view all
(2023)
Cleavage of cFLIP restrains cell death during viral infection and tissue injury and favors tissue repair.
Science Advances
, 9
(30)
, Article eadg2829. 10.1126/sciadv.adg2829.
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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.
| Type: | Article |
|---|---|
| Title: | Cleavage of cFLIP restrains cell death during viral infection and tissue injury and favors tissue repair |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1126/sciadv.adg2829 |
| Publisher version: | https://doi.org/10.1126/sciadv.adg2829 |
| Language: | English |
| Additional information: | Copyright © 2023 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution License 4.0 (CC BY). https://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution license, which permits which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Cancer Bio |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10214912 |
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