The anti-apoptotic protein c-FLIP, a catalytically inactive homolog of caspase-8, is an important regulator of death receptor signaling. Death receptors constitute a subgroup of the tumor necrosis factor receptor (TNFR) superfamily, which includes TNFR1, Fas, DR4, and DR5. When activated by their respective ligands, TNF, Fas ligand (FasL), and TNF-related apoptosis-inducing ligand (TRAIL), these receptors cause caspase-8–mediated apoptosis. If caspase-8 activity is blocked, however, then these receptors promote death by necroptosis (programmed necrosis), which requires the kinases receptor-interacting kinase 1 (RIPK1) and RIPK3, as well as mixed-lineage kinase-like protein. Necroptosis has become the subject of intense research because it promotes infl ammation, and inhibiting this pathway can limit extensive tissue damage and even lethality in infl ammatory syndromes. A study now reports on the role of c-FLIP in vivo from experiments with a range of condi- tional knockout mice and demonstrates that c-FLIP plays a critical role in inhibiting both apoptotic and necroptotic cell death within the whole mouse.
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