Catalytic activity of the caspase-8-FLIPL complex inhibits RIPK3-dependent necrosis

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 (FLIPL, also known as CFLAR), and this complex is required for the protective function.

• Publication year

  2011

• Venue

  Nature

• Publication date

  2011-02-08

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1038/nature09852PMID 21368763PMCID 3077893
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

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