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
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Animals
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Apoptosis
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Biocatalysis*
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CASP8 and FADD-Like Apoptosis Regulating Protein / metabolism*
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Caspase 8 / genetics
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Caspase 8 / metabolism*
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Caspase Inhibitors
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Cell Line
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Female
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Male
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Mice
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Multiprotein Complexes / chemistry
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Multiprotein Complexes / metabolism
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Necrosis*
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Phenotype
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Receptor-Interacting Protein Serine-Threonine Kinases / antagonists & inhibitors*
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Receptor-Interacting Protein Serine-Threonine Kinases / deficiency
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Receptor-Interacting Protein Serine-Threonine Kinases / genetics
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Receptor-Interacting Protein Serine-Threonine Kinases / metabolism*
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Serpins / pharmacology
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Tumor Necrosis Factor-alpha / antagonists & inhibitors
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Tumor Necrosis Factor-alpha / biosynthesis
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Tumor Necrosis Factor-alpha / pharmacology
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Viral Proteins / pharmacology
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fas Receptor / deficiency
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fas Receptor / metabolism
Substances
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CASP8 and FADD-Like Apoptosis Regulating Protein
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Caspase Inhibitors
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Cflar protein, mouse
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Multiprotein Complexes
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Serpins
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Tumor Necrosis Factor-alpha
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Viral Proteins
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fas Receptor
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interleukin-1beta-converting enzyme inhibitor
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Receptor-Interacting Protein Serine-Threonine Kinases
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Ripk3 protein, mouse
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Caspase 8