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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 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 kappa B 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.
Adaptor Proteins, Signal Transducing, Animals, Antigens, CD95/metabolism, Apoptosis/physiology, Apoptosis Regulatory Proteins, Carrier Proteins/metabolism, Caspase 8, Caspase 9, Caspases/metabolism, Cell Death/physiology, Fas Ligand Protein, Fas-Associated Death Domain Protein, Humans, Jurkat Cells, Membrane Glycoproteins/metabolism, Mice, Mice, Inbred BALB C, Models, Biological, Necrosis, Proteins/metabolism, Receptor-Interacting Protein Serine-Threonine Kinases, Signal Transduction, T-Lymphocytes/cytology, T-Lymphocytes/metabolism, TNF-Related Apoptosis-Inducing Ligand, Tumor Necrosis Factor-alpha/metabolism
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