Catalytic activity of the caspase-8-FLIP(L) complex inhibits RIPK3-dependent necrosis.

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.

• Authors: Andrew Oberst, Christopher P Dillon, Ricardo Weinlich, Laura L McCormick, Patrick Fitzgerald, Cristina Pop, Razq Hakem, Guy S Salvesen, Douglas R Green
• Journal: Nature (Nature) Vol. 471 Issue 7338 Pg. 363-7 (Mar 17 2011) ISSN: 1476-4687 [Electronic] England
• PMID: 21368763 (Publication Type: Journal Article)

Chemical References

• 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

Topics

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