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

N Holler, R Zaru, O Micheau, M Thome, A Attinger… - Nature …, 2000 - nature.com
N Holler, R Zaru, O Micheau, M Thome, A Attinger, S Valitutti, JL Bodmer, P Schneider
Nature immunology, 2000nature.com
Cell death is achieved by two fundamentally different mechanisms: apoptosis and necrosis.
Apoptosis is dependent on caspase activation, whereas the caspase-independent necrotic
signaling pathway remains largely uncharacterized. We show here that Fas 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
Fas ligand–induced caspase-independent death is absent in T cells that are deficient in …
Abstract
Cell death is achieved by two fundamentally different mechanisms: apoptosis and necrosis. Apoptosis is dependent on caspase activation, whereas the caspase-independent necrotic signaling pathway remains largely uncharacterized. We show here that Fas 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 Fas ligand–induced caspase-independent death is absent in T cells that are deficient in either Fas-associated death domain (FADD) or receptor-interacting protein (RIP). RIP is also required for necrotic death induced by tumor necrosis factor (TNF) and TNF-related apoptosis-inducing ligand (TRAIL). In contrast to its role in nuclear factor κB activation, RIP requires its own kinase activity for death signaling. Thus, Fas, TRAIL and TNF receptors can initiate cell death by two alternative pathways, one relying on caspase-8 and the other dependent on the kinase RIP.
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