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

Abstract

Caspase-8 mediates apoptosis induced by 'death receptors' on the cell's surface. At the same time, it is able to prevent receptor interacting protein kinase (RIPK)-dependent necrosis. Without caspase-8, mice die during embryonic development, but why this happens is not clear. Two groups show that this lethality is not caused by the absence of apoptosis, but by the RIPK3-dependent necrosis that is unleashed without caspase-8. Mice lacking both caspase-8 and RIP3 develop into viable, immunocompetent adults, but have a progressive lymphoaccumulative disease similar to that in mice that lack the CD95 death receptor. Oberst et al. also show that caspase-8 forms a proteolytically active complex with FLICE-like inhibitory protein long (FLIPL), and that this complex is required for protection against RIP3-dependent necrosis. Caspase-8 mediates apoptosis induced by death receptors. At the same time, this protease is able to prevent RIP-dependent necrosis. Without caspase-8 mice die during their embryonic development. Two papers now show that lethality is not caused by the absence of apoptosis, but by RIP3-dependent necrosis that is unleashed without caspase-8. Mice that lack both caspase-8 and RIP3 develop into viable, immunocompetent, fertile adult mice, but suffer from a progressive lymphoaccumulative disease similar to mice that lack the death receptor CD95. This paper further shows that caspase-8 forms a proteolytically active complex with FLIPL, and that this complex is required for protection against RIP3-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 development1, T-lymphocyte activation2, and resistance to necrosis induced by tumour necrosis factor-α (TNF-α) and related family ligands3,4. 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.