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

Journal article

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.

Authors: Macé, YM; Douanne, T; Jardine, J; Trillet, K; Moreau, R

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Springer
• Journal: EMBO Reports
• Publication date: 2026-07-15
• Acceptance date: 2026-07-06
• DOI: 10.1038/s44319-026-00876-4
• EISSN: 1469-3178
• ISSN: 1469-221X
• Language: English
• Keywords: Cell; Transcription factor; Programmed cell death; Mitochondrion; Signal transduction; Proteolysis; Deubiquitinating enzyme; Interferon; Apoptosis