RIPK1 blocks early postnatal lethality mediated by caspase-8 and RIPK3

Cell. 2014 May 22;157(5):1189-202. doi: 10.1016/j.cell.2014.04.018. Epub 2014 May 8.


Receptor-interacting protein kinase (RIPK)-1 is involved in RIPK3-dependent and -independent signaling pathways leading to cell death and/or inflammation. Genetic ablation of ripk1 causes postnatal lethality, which was not prevented by deletion of ripk3, caspase-8, or fadd. However, animals that lack RIPK1, RIPK3, and either caspase-8 or FADD survived weaning and matured normally. RIPK1 functions in vitro to limit caspase-8-dependent, TNFR-induced apoptosis, and animals lacking RIPK1, RIPK3, and TNFR1 survive to adulthood. The role of RIPK3 in promoting lethality in ripk1(-/-) mice suggests that RIPK3 activation is inhibited by RIPK1 postbirth. Whereas TNFR-induced RIPK3-dependent necroptosis requires RIPK1, cells lacking RIPK1 were sensitized to necroptosis triggered by poly I:C or interferons. Disruption of TLR (TRIF) or type I interferon (IFNAR) signaling delayed lethality in ripk1(-/-)tnfr1(-/-) mice. These results clarify the complex roles for RIPK1 in postnatal life and provide insights into the regulation of FADD-caspase-8 and RIPK3-MLKL signaling by RIPK1.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Vesicular Transport / metabolism
  • Animals
  • Animals, Newborn
  • Apoptosis
  • Caspase 8 / genetics
  • Caspase 8 / metabolism*
  • Cell Death
  • Embryo, Mammalian / cytology
  • Embryo, Mammalian / metabolism
  • Fas-Associated Death Domain Protein / metabolism
  • Fibroblasts / metabolism
  • Genes, Lethal*
  • Inflammation / metabolism
  • Interferons / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Receptor-Interacting Protein Serine-Threonine Kinases / genetics
  • Receptor-Interacting Protein Serine-Threonine Kinases / metabolism*
  • Receptors, Tumor Necrosis Factor, Type I / genetics
  • Receptors, Tumor Necrosis Factor, Type I / metabolism
  • Tumor Necrosis Factors / metabolism


  • Adaptor Proteins, Vesicular Transport
  • Fadd protein, mouse
  • Fas-Associated Death Domain Protein
  • Receptors, Tumor Necrosis Factor, Type I
  • TICAM-1 protein, mouse
  • Tnfrsf1a protein, mouse
  • Tumor Necrosis Factors
  • Interferons
  • Receptor-Interacting Protein Serine-Threonine Kinases
  • Ripk1 protein, mouse
  • Ripk3 protein, mouse
  • Casp8 protein, mouse
  • Caspase 8