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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Strasser, A., Jost, P. J. & Nagata, S. The many roles of FAS receptor signaling in the immune system. Immunity 30, 180–192 (2009)
Cho, Y. S. et al. Phosphorylation-driven assembly of the RIP1–RIP3 complex regulates programmed necrosis and virus-induced inflammation. Cell 137, 1112–1123 (2009)
He, S. et al. Receptor interacting protein kinase-3 determines cellular necrotic response to TNF-α. Cell 137, 1100–1111 (2009)
Zhang, D. W. et al. RIP3, an energy metabolism regulator that switches TNF-induced cell death from apoptosis to necrosis. Science 325, 332–336 (2009)
Holler, N. et al. Fas triggers an alternative, caspase-8-independent cell death pathway using the kinase RIP as effector molecule. Nature Immunol. 1, 489–495 (2000)
Upton, J. W., Kaiser, W. J. & Mocarski, E. S. Virus inhibition of RIP3-dependent necrosis. Cell Host Microbe 7, 302–313 (2010)
Varfolomeev, E. E. et al. Targeted disruption of the mouse Caspase 8 gene ablates cell death induction by the TNF receptors, Fas/Apo1, and DR3 and is lethal prenatally. Immunity 9, 267–276 (1998)
Chan, F. K. et al. A role for tumor necrosis factor receptor-2 and receptor-interacting protein in programmed necrosis and antiviral responses. J. Biol. Chem. 278, 51613–51621 (2003)
Yu, L. et al. Regulation of an ATG7-beclin 1 program of autophagic cell death by caspase-8. Science 304, 1500–1502 (2004)
McCormick, A. L., Skaletskaya, A., Barry, P. A., Mocarski, E. S. & Goldmacher, V. S. Differential function and expression of the viral inhibitor of caspase 8-induced apoptosis (vICA) and the viral mitochondria-localized inhibitor of apoptosis (vMIA) cell death suppressors conserved in primate and rodent cytomegaloviruses. Virology 316, 221–233 (2003)
Kang, T. B. et al. Caspase-8 serves both apoptotic and nonapoptotic roles. J. Immunol. 173, 2976–2984 (2004)
Kang, T. B. et al. Mutation of a self-processing site in caspase-8 compromises its apoptotic but not its nonapoptotic functions in bacterial artificial chromosome-transgenic mice. J. Immunol. 181, 2522–2532 (2008)
Sakamaki, K. et al. Ex vivo whole-embryo culture of caspase-8-deficient embryos normalize their aberrant phenotypes in the developing neural tube and heart. Cell Death Differ. 9, 1196–1206 (2002)
Salmena, L. et al. Essential role for caspase 8 in T-cell homeostasis and T-cell-mediated immunity. Genes Dev. 17, 883–895 (2003)
Mitjavila-Garcia, M. T. et al. Expression of CD41 on hematopoietic progenitors derived from embryonic hematopoietic cells. Development 129, 2003–2013 (2002)
Kovalenko, A. et al. Caspase-8 deficiency in epidermal keratinocytes triggers an inflammatory skin disease. J. Exp. Med. 206, 2161–2177 (2009)
Lee, P. et al. Dynamic expression of epidermal caspase 8 simulates a wound healing response. Nature 458, 519–523 (2009)
Kaufmann, T. et al. Fatal hepatitis mediated by tumor necrosis factor TNFα requires caspase-8 and involves the BH3-only proteins Bid and Bim. Immunity 30, 56–66 (2009)
Hoebe, K. et al. Identification of Lps2 as a key transducer of MyD88-independent TIR signalling. Nature 424, 743–748 (2003)
Newton, K., Sun, X. & Dixit, V. M. Kinase RIP3 is dispensable for normal NF-κBs, signaling by the B-cell and T-cell receptors, tumor necrosis factor receptor 1, and Toll-like receptors 2 and 4. Mol. Cell. Biol. 24, 1464–1469 (2004)
Beisner, D. R., Ch’en, I. L., Kolla, R. V., Hoffmann, A. & Hedrick, S. M. Cutting edge: innate immunity conferred by B cells is regulated by caspase-8. J. Immunol. 175, 3469–3473 (2005)
Salmena, L. & Hakem, R. Caspase-8 deficiency in T cells leads to a lethal lymphoinfiltrative immune disorder. J. Exp. Med. 202, 727–732 (2005)
Bidere, N., Su, H. C. & Lenardo, M. J. Genetic disorders of programmed cell death in the immune system. Annu. Rev. Immunol. 24, 321–352 (2006)
Ch’en, I. L. et al. Antigen-mediated T cell expansion regulated by parallel pathways of death. Proc. Natl Acad. Sci. USA 105, 17463–17468 (2008)
Laouar, Y. & Ezine, S. In vivo CD4+ lymph node T cells from lpr mice generate CD4–CD8-B220+TCR-beta low cells. J. Immunol. 153, 3948–3955 (1994)
Ventura, A. et al. Restoration of p53 function leads to tumour regression in vivo . Nature 445, 661–665 (2007)
Kaiser, W. J. & Offermann, M. K. Apoptosis induced by the toll-like receptor adaptor TRIF is dependent on its receptor interacting protein homotypic interaction motif. J. Immunol. 174, 4942–4952 (2005)
Belo, J. A. et al. Cerberus-like is a secreted factor with neutralizing activity expressed in the anterior primitive endoderm of the mouse gastrula. Mech. Dev. 68, 45–57 (1997)
Sarbassov, D. D., Guertin, D. A., Ali, S. M. & Sabatini, D. M. Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science 307, 1098–1101 (2005)
Kaiser, W. J., Upton, J. W. & Mocarski, E. S. Receptor-interacting protein homotypic interaction motif-dependent control of NF-κB activation via the DNA-dependent activator of IFN regulatory factors. J. Immunol. 181, 6427–6434 (2008)
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.).
The authors declare no competing financial interests.
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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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