RIP3 mediates the embryonic lethality of caspase-8-deficient mice

By William J. Kaiser, J. Upton, Alyssa B. Long, D. Livingston-Rosanoff, L. Daley, R. Hakem, Tamara Caspary, E. Mocarski. Nature, 2011

1,054 citations recorded by the source corpus.

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.

Subfields: Immunology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/f6be28bf43a0221c1ee5928a69c6a40090ad6c3b

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Citations in the corpus

A guide to cell death pathways (2023, positive): “Furthermore, blocking RIPK1 kinase and necroptosis can suppress early embryonic lethality of Casp8 -null mice, Fadd -null mice, Abin1 -null mice and Tbk1 - null mice, suggesting that necroptosis may be involved in the removal of defective developing embryos 52,67,139,140 .”
DAI complexes with RIP3 to mediate virus-induced programmed necrosis that is targeted by murine cytomegalovirus vIRA (2012, positive): “Likewise, the RIP3-dependent necroptosis resulting in lethality of Casp8−/− mice (Kaiser et al., 2011; Oberst et al., 2011) was not rescued loss of DAI (Figure S3D), and Casp8−/−DAI−/− embryos were phenotypically indistinguishable from Casp8−/− littermate embryos (data not shown).”
The Ripoptosome, a signaling platform that assembles in response to genotoxic stress and loss of IAPs. (2011, background): “…that FADD, caspase-8, and FLIP, which resembles caspase-8 but lacks a catalytically active residue (Wilson et al., 2009), are required for embryonic development and T-lymphocyte activation by inhibiting RIP-dependent necrosis (Gentle et al., 2011; Kaiser et al., 2011; Oberst et al., 2011).”
The RIP1/RIP3 Necrosome Forms a Functional Amyloid Signaling Complex Required for Programmed Necrosis (2012, neutral): “…critical for preventing extensive necrosis during embryonic development in order to ensure proper clonal expansion of lymphocytes and to prevent extensive necrosis and inflammation in skin and intestinal epithelium (Kaiser et al., 2011; Oberst et al., 2011; Welz et al., 2011; Zhang et al., 2011).”
Caspase-8 regulates TNF-alpha induced epithelial necroptosis and terminal ileitis (2011, positive): “This has been highlighted by genetic studies demonstrating that deletion of RIP3 can rescue the embryonic lethality observed in mice with a general deletion of caspase-8 19,20 .”
Mixed lineage kinase domain-like protein mediates necrosis signaling downstream of RIP3 kinase. (2012, neutral): “This indicates that the cardiac, vascular, and hematopoietic defects that occur during the development of caspase-8 knockout mice are caused by RIP3-mediated necrosis, unleashed by disrupting caspase-8 expression (Kaiser et al., 2011; Oberst et al., 2011).”