Caspase-3 cleaves CYLD to restrict interferon signaling during mitochondrial apoptosis

  • EMBO Rep. 2026 Jul 15. doi: 10.1038/s44319-026-00876-4.
Yanis M Macé  1  2 ,  Tiphaine Douanne  1  2 ,  Jane Jardine  1  2 ,  Kilian Trillet  1  2 ,  Rosalie Moreau  1  2 ,  Joanna Re  3 ,  Cara J Ellison  4 ,  Nadine Laguette  3 ,  Paul R Elliott  4 ,  Julie Gavard  1  2  5 ,  Nicolas Bidère  6  7
Affiliations
  • 1. Team SOAP, CRCI²NA, INSERM, CNRS, Université de Nantes, Nantes, France.
  • 2. Equipe Labellisée Ligue Contre le Cancer, Paris, France.
  • 3. Institut de Génétique Moléculaire de Montpellier (IGMM), Université de Montpellier, CNRS UMR5535, Montpellier, France.
  • 4. Department of Biochemistry, University of Oxford, Oxford, UK.
  • 5. Institut de Cancérologie de l'Ouest (ICO), Saint-Herblain, France.
  • 6. Team SOAP, CRCI²NA, INSERM, CNRS, Université de Nantes, Nantes, France. [email protected].
  • 7. Equipe Labellisée Ligue Contre le Cancer, Paris, France. [email protected].
PMID: 42458071 DOI: 10.1038/s44319-026-00876-4
Abstract

Mitochondrial outer membrane permeabilization is a pivotal event in programmed cell death by Apoptosis, leading to the activation of the cysteine protease Caspase-3 (CASP3) and the release of mitochondrial nucleic acids. This release triggers the activation of the Interferon Regulatory Factor 3 (IRF3) transcription factor and the subsequent IRF3-mediated type I interferon production and cell death. CASP3 ensures Apoptosis remains immunologically silent, though the mechanisms are unclear. We report that CASP3 cleaves CYLD, a deubiquitinating enzyme crucial for cell fate and inflammatory signaling. This proteolysis occurs at a site distinct from the previously reported CASP8 site, which is involved in limiting Cell Lysis and inflammation during extrinsic Apoptosis. Although cleaved CYLD retains its enzymatic activity in vitro, knocked-in cells expressing CASP3-resistant CYLD show increased interferon signaling and enhanced cell death. Thus, a proteolytic code regulates CYLD to balance inflammation during programmed cell death.

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