Cited by 494Cell death mechanisms and regulationNF-κB Signaling PathwaysInflammasome and immune disorders

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Caspase 8 inhibits programmed necrosis by processing CYLD

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O’Donnell, Marie Anne, Perez-Jimenez, Eva, Oberst, Andrew, Ng, Aylwin, Massoumi, Ramin, Xavier, Ramnik, Green, Douglas R., Ting, Adrian T.·2011·Nature Cell Biology

DOI 10.1038/ncb2362PMC PMC3229661

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Abstract

Caspase 8 initiates apoptosis downstream of TNF death receptors by undergoing autocleavage and processing the executioner caspase 3 (ref. 1). However, the dominant function of caspase 8 is to transmit a pro-survival signal that suppresses programmed necrosis (or necroptosis) mediated by RIPK1 and RIPK3 (refs 2-6) during embryogenesis and haematopoiesis(7-9). Suppression of necrotic cell death by caspase 8 requires its catalytic activity but not the autocleavage essential for apoptosis(10); however, the key substrate processed by caspase 8 to block necrosis has been elusive. A key substrate must meet three criteria: it must be essential for programmed necrosis; it must be cleaved by caspase 8 in situations where caspase 8 is blocking necrosis; and mutation of the caspase 8 processing site on the substrate should convert a pro-survival response to necrotic death without the need for caspase 8 inhibition. We now identify CYLD as a substrate for caspase 8 that satisfies these criteria. Following TNF stimulation, caspase 8 cleaves CYLD to generate a survival signal. In contrast, loss of caspase 8 prevented CYLD degradation, resulting in necrotic death. A CYLD substitution mutation at Asp 215 that cannot be cleaved by caspase 8 switches cell survival to necrotic cell death in response to TNF.

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Authors: O’Donnell, M. A., Perez-Jimenez, E., Oberst, A., Ng, A., Massoumi, R., Xavier, R., Green, D. R., & Ting, A. T.
Affiliations: Icahn School of Medicine at Mount Sinai (US)
St. Jude Children's Research Hospital (US)
Harvard University (US)
Lund University (SE)
Corresponding author: O’Donnell, Marie Anne
Ting, Adrian T.
ORCID: O’Donnell, Marie Anne
Oberst, Andrew
Massoumi, Ramin
Xavier, Ramnik
Green, Douglas R.
Ting, Adrian T.
Venue: Nature Cell Biology
Publisher: Springer Science and Business Media LLC
Published: 2011-10-30
Volume: 13
Issue: 12
Pages: 1437-1442
ISSN: 1465-7392 (ISSN-L)
1476-4679
DOI: 10.1038/ncb2362
PMC: PMC3229661
OpenAlex: W2091802222
Cited by: 494
References: 33
Citations by year: 2026: 23 · 2025: 27 · 2024: 30 · 2023: 25 · 2022: 23 · 2021: 33 · 2020: 28 · 2019: 36 · 2018: 22 · 2017: 29 · 2016: 48 · 2015: 34 · 2014: 61 · 2013: 39 · 2012: 31
FWCI: 17.51
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: www.springer.com/tdm (tdm)
Locations: Nature Cell Biology (publishedVersion)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
Lund University Publications (Lund University) (submittedVersion)
Funders: National Institute of General Medical Sciences (R01GM052735)
National Institute of Allergy and Infectious Diseases (R01AI044828, AI052417, R56AI052417, R01AI052417, AI44828, R37AI044828)
National Institute of Diabetes and Digestive and Kidney Diseases (P30DK043351)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
Keywords: caspase-8, CYLD, necroptosis, RIPK1, RIPK3, TNF signaling, cell survival signaling, embryonic development, hematopoiesis
MeSH terms: Deubiquitinating Enzyme CYLD, Animals, Cell Survival, Cells, Cultured, Embryo, Mammalian, Female, Fibroblasts, Humans, Necrosis, Protein Processing, Post-Translational, Signal Transduction, Jurkat Cells, Tumor Suppressor Proteins, Mice, Caspase 8, HEK293 Cells

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Caspase 8 inhibits programmed necrosis by processing CYLD

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