RIP3 Mediates the Embryonic Lethality of caspase-8-deficient Mice

Nature. 2011 Mar 17;471(7338):368-72. doi: 10.1038/nature09857. Epub 2011 Mar 2.

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 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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Apoptosis*
  • Caspase 8 / genetics*
  • Caspase 8 / metabolism*
  • Caspase Inhibitors
  • Cell Line
  • Embryo Loss / enzymology
  • Embryo Loss / genetics*
  • Embryo Loss / metabolism*
  • Embryo, Mammalian / cytology
  • Embryo, Mammalian / embryology
  • Female
  • GTPase-Activating Proteins / metabolism
  • Gene Deletion*
  • Immunocompetence / genetics
  • Immunocompetence / immunology
  • Lymphatic Diseases / genetics
  • Lymphatic Diseases / immunology
  • Lymphatic Diseases / pathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Necrosis*
  • Receptor-Interacting Protein Serine-Threonine Kinases / antagonists & inhibitors
  • Receptor-Interacting Protein Serine-Threonine Kinases / deficiency
  • Receptor-Interacting Protein Serine-Threonine Kinases / genetics
  • Receptor-Interacting Protein Serine-Threonine Kinases / metabolism*

Substances

  • Caspase Inhibitors
  • GTPase-Activating Proteins
  • Ralbp1 protein, mouse
  • Receptor-Interacting Protein Serine-Threonine Kinases
  • Ripk3 protein, mouse
  • Caspase 8