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

Publikation: Beitrag in FachzeitschriftForschungsartikelBeigetragenBegutachtung


  • Kristel Martinez Lagunas - , Deutsche Sporthochschule Köln (Autor:in)
  • Deniz Pinar Savcigil - , Deutsche Sporthochschule Köln (Autor:in)
  • Matea Zrilic - , Deutsche Sporthochschule Köln (Autor:in)
  • Carlos Carvajal Fraile - , Deutsche Sporthochschule Köln (Autor:in)
  • Andrew Craxton - , University of Cambridge (Autor:in)
  • Emily Self - , University of Cambridge (Autor:in)
  • Iratxe Uranga-Murillo - , Aragón Health Research Institute (Autor:in)
  • Diego de Miguel - , Aragón Health Research Institute (Autor:in)
  • Maykel Arias - , Aragón Health Research Institute (Autor:in)
  • Sebastian Willenborg - , Deutsche Sporthochschule Köln (Autor:in)
  • Michael Piekarek - , Deutsche Sporthochschule Köln (Autor:in)
  • Marie Christine Albert - , Deutsche Sporthochschule Köln (Autor:in)
  • Kalvin Nugraha - , Deutsche Sporthochschule Köln (Autor:in)
  • Ina Lisewski - , Deutsche Sporthochschule Köln (Autor:in)
  • Erika Janakova - , Deutsche Sporthochschule Köln (Autor:in)
  • Natalia Igual - , Deutsche Sporthochschule Köln (Autor:in)
  • Wulf Tonnus - , Biotechnologisches Zentrum (BIOTEC), Medizinische Klinik und Poliklinik 3, Universitätsklinikum Carl Gustav Carus Dresden (Autor:in)
  • Ximena Hildebrandt - , Deutsche Sporthochschule Köln (Autor:in)
  • Mohammed Ibrahim - , Deutsche Sporthochschule Köln (Autor:in)
  • Marlies Ballegeer - , VIB-UGent Center for Medical Biotechnology (Autor:in)
  • Xavier Saelens - , VIB-UGent Center for Medical Biotechnology (Autor:in)
  • Andrew Kueh - , Walter and Eliza Hall Institute of Medical Research (WEHI) (Autor:in)
  • Pascal Meier - , Institute of Cancer Research (Autor:in)
  • Andreas Linkermann - , Biotechnologisches Zentrum (BIOTEC), Medizinische Klinik und Poliklinik 3, Universitätsklinikum Carl Gustav Carus Dresden, Albert Einstein College of Medicine (Autor:in)
  • Julian Pardo - , Aragón Health Research Institute (Autor:in)
  • Sabine Eming - , Deutsche Sporthochschule Köln (Autor:in)
  • Henning Walczak - , Deutsche Sporthochschule Köln (Autor:in)
  • Marion MacFarlane - , University of Cambridge (Autor:in)
  • Nieves Peltzer - , Deutsche Sporthochschule Köln (Autor:in)
  • Alessandro Annibaldi - , Deutsche Sporthochschule Köln (Autor:in)


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.


FachzeitschriftScience advances
Jahrgang9 (2023)
PublikationsstatusVeröffentlicht - 26 Juli 2023

Externe IDs

PubMedCentral PMC10371024
Scopus 85165870244
ORCID /0000-0001-6287-9725/work/145698871
ORCID /0000-0002-9728-1413/work/145699145



  • Animals, Mice, Caspase 8/genetics, Apoptosis, Skin/metabolism, Tumor Necrosis Factor-alpha/metabolism, Virus Diseases