Cleavage of CFLIP Restrains Cell Death During Viral Infection and Tissue Injury and Favors Tissue Repair

Overview

Journal Sci Adv

Specialties Biology
Science

Date 2023 Jul 26

PMID 37494451

Authors

Kristel Martinez Lagunas

Deniz Pinar Savcigil

Matea Zrilic

Carlos Carvajal Fraile

Andrew Craxton

Emily Self

Iratxe Uranga-Murillo

Diego de Miguel

Maykel Arias

Sebastian Willenborg

Michael Piekarek

Marie Christine Albert

Kalvin Nugraha

Ina Lisewski

Erika Janakova

Natalia Igual

Wulf Tonnus

Ximena Hildebrandt

Mohammed Ibrahim

Marlies Ballegeer

Xavier Saelens

Andrew Kueh

Pascal Meier

Andreas Linkermann

Julian Pardo

Sabine Eming

Henning Walczak

Marion MacFarlane

Nieves Peltzer

Alessandro Annibaldi

Affiliations

Soon will be listed here.

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, , exhibited increased sensitivity to severe acute respiratory syndrome coronavirus (SARS-CoV)-induced lethality, impaired skin wound healing, and increased tissue damage caused by 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.

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