Fas triggers an alternative, caspase-8-independent cell death pathway using the kinase RIP as effector molecule

Cell death is achieved by two fundamentally different mechanisms: apoptosis and necrosis,Apoptosis is dependent on caspase activation, whereas the cas pase-independent necrotic signaling pathway remains largely uncharacterized . We show here that Pas kills activated primary T cells efficiently in the absence of active caspases, which results in necrotic morphological changes and late mitochondrial damage but no cytochrome c release,This Pas ligand- induced caspase-independent death is absent in T cells that are deficient i n either Fas-associated death domain (FADD) or receptor-interacting protein (RIP), RIP is also required for necrotic death induced by tumor necrosis f actor (INF) and TNF-related apoptosis-inducing ligand (TRAIL), In contrast to its role in nuclear factor kappaB activation, RIP requires its own kinas e activity for death signaling. Thus, pas, TRAIL and TNF receptors can init iate cell death by two alternative pathways, one relying on caspase-8 and t he other dependent on the kinase RIP.