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

Research output: Contribution to journalResearch articleContributedpeer-review


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


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.


Original languageEnglish
Article numbereadg2829
Pages (from-to)eadg2829
JournalScience advances
Issue number30
Publication statusPublished - 28 Jul 2023

External 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