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RIP3 mediates the embryonic lethality of caspase-8-deficient mice
Open accessAbstract
Apoptosis and necroptosis are complementary pathways controlled by common signalling adaptors, kinases and proteases; among these, caspase-8 (Casp8) is critical for death receptor-induced apoptosis. This caspase has also been implicated in non-apoptotic pathways that regulate Fas-associated via death domain (FADD)-dependent signalling and other less defined biological processes as diverse as innate immune signalling and myeloid or lymphoid differentiation patterns. Casp8 suppresses RIP3-RIP1 (also known as RIPK3-RIPK1) kinase complex-dependent necroptosis that follows death receptor activation as well as a RIP3-dependent, RIP1-independent necrotic pathway that has emerged as a host defence mechanism against murine cytomegalovirus. Disruption of Casp8 expression leads to embryonic lethality in mice between embryonic days 10.5 and 11.5 (ref. 7). Thus, Casp8 may naturally hold alternative RIP3-dependent death pathways in check in addition to promoting apoptosis. We find that RIP3 is responsible for the mid-gestational death of Casp8-deficient embryos. Remarkably, Casp8(-/-)Rip3(-/-) double mutant mice are viable and mature into fertile adults with a full immune complement of myeloid and lymphoid cell types. These mice seem immunocompetent but develop lymphadenopathy by four months of age marked by accumulation of abnormal T cells in the periphery, a phenotype reminiscent of mice with Fas-deficiency (lpr/lpr; also known as Fas). Thus, Casp8 contributes to homeostatic control in the adult immune system; however, RIP3 and Casp8 are together completely dispensable for mammalian development.
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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 [478]
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Metadata
- Authors
- Kaiser, W. J., Upton, J. W., Long, A. B., Livingston-Rosanoff, D., Daley-Bauer, L. P., Hakem, R., Caspary, T., & Mocarski, E. S.
- Affiliations
- Emory University (US)
- University Health Network (CA)
- Corresponding author
- Kaiser, William J.
- ORCID
- Venue
- Nature
- Published
- 2011-03
- Volume
- 471
- Issue
- 7338
- Pages
- 368-372
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC3060292
- OpenAlex
- W2042577315
- Cited by
- 1,057
- References
- 31
- Citations by year
- 2026: 37 · 2025: 60 · 2024: 56 · 2023: 51 · 2022: 66 · 2021: 61 · 2020: 70 · 2019: 55 · 2018: 68 · 2017: 59 · 2016: 88 · 2015: 75 · 2014: 120 · 2013: 69 · 2012: 71
- FWCI
- 40.08
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Georgia Cancer Coalition
- National Institutes of Health (DP5OD012198)
- National Institute of General Medical Sciences (T32GM008169)
- National Institute of Allergy and Infectious Diseases (R01AI030363, R01AI20211, R01AI020211, R56AI030363, R21AI030363, AI30363)
- 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, necroptosis, embryonic lethality, death receptor signaling, FADD, Fas, RIPK1, apoptosis, lymphoid development, innate immunity, programmed cell death
- MeSH terms
- Animals, Cell Line, Embryo, Mammalian, Female, Immunocompetence, Lymphatic Diseases, Male, Mice, Inbred C57BL, Necrosis, Apoptosis, Gene Deletion, Mice, Knockout, GTPase-Activating Proteins, Embryo Loss, Mice, Caspase 8, Receptor-Interacting Protein Serine-Threonine Kinases, Caspase Inhibitors
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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