Catalytic Activity of the caspase-8-FLIP(L) Complex Inhibits RIPK3-dependent Necrosis

Nature. 2011 Mar 17;471(7338):363-7. doi: 10.1038/nature09852. Epub 2011 Mar 2.

Abstract

Caspase-8 has two opposing biological functions--it promotes cell death by triggering the extrinsic pathway of apoptosis, but also has a survival activity, as it is required for embryonic development, T-lymphocyte activation, and resistance to necrosis induced by tumour necrosis factor-α (TNF-α) and related family ligands. Here we show that development of caspase-8-deficient mice is completely rescued by ablation of receptor interacting protein kinase-3 (RIPK3). Adult animals lacking both caspase-8 and RIPK3 display a progressive lymphoaccumulative disease resembling that seen with defects in CD95 or CD95-ligand (also known as FAS and FASLG, respectively), and resist the lethal effects of CD95 ligation in vivo. We have found that caspase-8 prevents RIPK3-dependent necrosis without inducing apoptosis by functioning in a proteolytically active complex with FLICE-like inhibitory protein long (FLIP(L), also known as CFLAR), and this complex is required for the protective function.

MeSH terms

  • Animals
  • Apoptosis
  • Biocatalysis*
  • CASP8 and FADD-Like Apoptosis Regulating Protein / metabolism*
  • Caspase 8 / genetics
  • Caspase 8 / metabolism*
  • Caspase Inhibitors
  • Cell Line
  • Female
  • Male
  • Mice
  • Multiprotein Complexes / chemistry
  • Multiprotein Complexes / metabolism
  • Necrosis*
  • Phenotype
  • 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*
  • Serpins / pharmacology
  • Tumor Necrosis Factor-alpha / antagonists & inhibitors
  • Tumor Necrosis Factor-alpha / biosynthesis
  • Tumor Necrosis Factor-alpha / pharmacology
  • Viral Proteins / pharmacology
  • fas Receptor / deficiency
  • fas Receptor / metabolism

Substances

  • CASP8 and FADD-Like Apoptosis Regulating Protein
  • Caspase Inhibitors
  • Cflar protein, mouse
  • Multiprotein Complexes
  • Serpins
  • Tumor Necrosis Factor-alpha
  • Viral Proteins
  • fas Receptor
  • interleukin-1beta-converting enzyme inhibitor
  • Receptor-Interacting Protein Serine-Threonine Kinases
  • Ripk3 protein, mouse
  • Caspase 8