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Survival function of the FADD-CASPASE-8-cFLIP(L) complex

Cell Rep. 2012 May 31;1(5):401-7. doi: 10.1016/j.celrep.2012.03.010.

Abstract

Caspase-8, the initiator caspase of the death receptor pathway of apoptosis, its adapter molecule, FADD, required for caspase-8 activation, and cFLIPL, a caspase-8-like protein that lacks a catalytic site and blocks caspase-8-mediated apoptosis, are each essential for embryonic development. Animals deficient in any of these genes present with E10.5 embryonic lethality. Recent studies have shown that development in caspase-8-deficient mice is rescued by ablation of RIPK3, a kinase that promotes a form of programmed, necrotic cell death. Here, we show that FADD, RIPK3 double-knockout mice develop normally but that the lethal effects of cFLIP deletion are not rescued by RIPK3 deficiency. Remarkably, in mice lacking FADD, cFLIP, and RIPK3, embryonic development is normal. This can be explained by the convergence of two cell processes: the enzymatic activity of the FADD-caspase-8-cFLIPL complex blocks RIPK3-dependent signaling (including necrosis), whereas cFLIPL blocks RIPK3-independent apoptosis promoted by the FADD-caspase-8 complex.

Publication types

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

MeSH terms

  • Animals
  • Apoptosis / genetics
  • Apoptosis / physiology
  • CASP8 and FADD-Like Apoptosis Regulating Protein / deficiency
  • CASP8 and FADD-Like Apoptosis Regulating Protein / genetics
  • CASP8 and FADD-Like Apoptosis Regulating Protein / physiology*
  • Caspase 8 / genetics
  • Caspase 8 / physiology*
  • Embryonic Development / genetics
  • Embryonic Development / physiology*
  • Fas-Associated Death Domain Protein / deficiency
  • Fas-Associated Death Domain Protein / genetics
  • Fas-Associated Death Domain Protein / physiology*
  • Gene Deletion
  • Mice
  • Mice, Knockout
  • Necrosis / genetics
  • Necrosis / physiopathology
  • Receptor-Interacting Protein Serine-Threonine Kinases / deficiency
  • Receptor-Interacting Protein Serine-Threonine Kinases / genetics
  • Receptor-Interacting Protein Serine-Threonine Kinases / physiology
  • Signal Transduction / genetics
  • Signal Transduction / physiology*

Substances

  • CASP8 and FADD-Like Apoptosis Regulating Protein
  • Fadd protein, mouse
  • Fas-Associated Death Domain Protein
  • Receptor-Interacting Protein Serine-Threonine Kinases
  • Ripk3 protein, mouse
  • Caspase 8