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Catalytic activity of the caspase-8–FLIPL complex inhibits RIPK3-dependent necrosis
Open accessAbstract
Caspase-8 has two opposing biological functions--it promotes cell death by triggering the extrinsic pathway of apoptosis, but also has a survival activity, as it is required for embryonic development, T-lymphocyte activation, and resistance to necrosis induced by tumour necrosis factor-α (TNF-α) and related family ligands. Here we show that development of caspase-8-deficient mice is completely rescued by ablation of receptor interacting protein kinase-3 (RIPK3). Adult animals lacking both caspase-8 and RIPK3 display a progressive lymphoaccumulative disease resembling that seen with defects in CD95 or CD95-ligand (also known as FAS and FASLG, respectively), and resist the lethal effects of CD95 ligation in vivo. We have found that caspase-8 prevents RIPK3-dependent necrosis without inducing apoptosis by functioning in a proteolytically active complex with FLICE-like inhibitory protein long (FLIP(L), also known as CFLAR), and this complex is required for the protective function.
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“In addition, the assembly of the necrosome upon TNFR1 stimulation impinges on two conditions: (1) pharmacological or genetic CASP8 inactivation [478, 479], and (2) RIPK1 deubiquitination-dependent phosphorylation (at least in some settings), which can be favored by exogenously provided SMAC mimetics, ensuring the release of RIPK1 from complex I (see above) [334, 335, 480, 481].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [479]
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“org 3 deletion of Rip3 (49, 50) or Cyld (51), suggesting that caspase8 exerted an antinecroptotic effect by cleaving RIP3 or CYLD.”
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Metadata
- Authors
- Oberst, A., Dillon, C. P., Weinlich, R., McCormick, L. L., Fitzgerald, P., Pop, C., Hakem, R., Salvesen, G. S., & Green, D. R.
- Affiliations
- St. Jude Children's Research Hospital (US)
- Sanford Burnham Prebys Medical Discovery Institute (US)
- Corresponding author
- Green, Douglas R.
- ORCID
- Venue
- Nature
- Published
- 2011-03-02
- Volume
- 471
- Issue
- 7338
- Pages
- 363-367
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC3077893
- OpenAlex
- W1975593978
- Cited by
- 1,278
- References
- 32
- Citations by year
- 2026: 49 · 2025: 68 · 2024: 84 · 2023: 69 · 2022: 88 · 2021: 81 · 2020: 88 · 2019: 71 · 2018: 87 · 2017: 80 · 2016: 102 · 2015: 83 · 2014: 116 · 2013: 81 · 2012: 81
- FWCI
- 42.03
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Ariad Pharmaceuticals
- National Institutes of Health
- Canadian Institutes of Health Research
- National Cancer Institute (P01CA069381)
- National Institute of Allergy and Infectious Diseases (R01AI044828, R37AI044828)
- 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, RIPK3, necroptosis, apoptosis, death receptors, Fas, embryonic lethality, Fas ligand, TNF-alpha resistance, cell death regulation, proteolytic complex, lymphocyte activation
- MeSH terms
- Animals, Cell Line, Female, Male, Necrosis, Phenotype, Tumor Necrosis Factor-alpha, Viral Proteins, Serpins, Apoptosis, fas Receptor, Multiprotein Complexes, Mice, Caspase 8, Receptor-Interacting Protein Serine-Threonine Kinases, CASP8 and FADD-Like Apoptosis Regulating Protein, Biocatalysis, Caspase Inhibitors
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