Abstract
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 patterns1. Casp8 suppresses RIP3–RIP1 (also known as RIPK3–RIPK1) kinase complex-dependent2,3,4 necroptosis5 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 cytomegalovirus6. 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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Acknowledgements
We acknowledge D. Green, A. Oberst and C. Dillon for their discussions and material support. We thank V. Dixit and K. Newton for RIP3−/− mice, A. Kowalczyk, R. Oas, S. Speck and R. Ahmed for providing reagents, T. Kaufmann for technical advice, C. Strauss for editing, and A. L. McCormick for discussion and comments on the manuscript. Additionally, we appreciate M. Dowdy and J. Perry for mouse colony maintenance. This work was supported by the Georgia Cancer Coalition and the NIH (PHS grants R01 AI20211 and AI30363 to E.S.M.).
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W.J.K., J.W.U., L.P.D.-B., and D.L.-R. designed and performed experiments and assembled figure panels. A.B.L. and T.C. guided evaluation of embryos. R.H. provided essential material support. E.S.M. supervised the project. W.J.K. and E.S.M. wrote the manuscript. T.C., R.H., J.W.U., L.P.D.-B., and D.L.-R. edited the text and figures during assembly of the manuscript.
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Kaiser, W., Upton, J., Long, A. et al. RIP3 mediates the embryonic lethality of caspase-8-deficient mice. Nature 471, 368–372 (2011). https://doi.org/10.1038/nature09857
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DOI: https://doi.org/10.1038/nature09857
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