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

• Published in: Science advances Vol. 9; no. 30; p. eadg2829
• Main Authors: Martinez Lagunas, Kristel, Savcigil, Deniz Pinar, Zrilic, Matea, Carvajal Fraile, Carlos, Craxton, Andrew, Self, Emily, Uranga-Murillo, Iratxe, de Miguel, Diego, Arias, Maykel, Willenborg, Sebastian, Piekarek, Michael, Albert, Marie Christine, Nugraha, Kalvin, Lisewski, Ina, Janakova, Erika, Igual, Natalia, Tonnus, Wulf, Hildebrandt, Ximena, Ibrahim, Mohammed, Ballegeer, Marlies, Saelens, Xavier, Kueh, Andrew, Meier, Pascal, Linkermann, Andreas, Pardo, Julian, Eming, Sabine, Walczak, Henning, MacFarlane, Marion, Peltzer, Nieves, Annibaldi, Alessandro
• Format: Journal Article
• Language: English
• Published: United States American Association for the Advancement of Science 28.07.2023
• Subjects: Animals; Apoptosis; Biomedicine and Life Sciences; Caspase 8 - genetics; Cell Biology; Immunology; Mice; SciAdv r-articles; Skin - metabolism; Tumor Necrosis Factor-alpha - metabolism; Virus Diseases
• ISSN: 2375-2548; 2375-2548
• DOI: 10.1126/sciadv.adg2829

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. cFLIP cleavage acts as a molecular brake on cell death and is essential for the ability of tissues to overcome damage.