Caspase 8 inhibits programmed necrosis by processing CYLD
Open accessAbstract
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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Necroptosis relies on deubiquitinating activity of CYLD, which is also proteolytic target of CASP8.
“Accordingly, necroptosis relies on the deubiquitinating activity of CYLD [338], which is also a proteolytic target of CASP8 [494–496].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [496]
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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
- Venue
- Nature Cell Biology
- Published
- 2011-10-30
- Volume
- 13
- Issue
- 12
- Pages
- 1437-1442
- ISSN
- 1465-7392 (ISSN-L)
- 1476-4679
- 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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