Membrane-bound Fas ligand requires RIP1 for efficient activation of caspase-8 within the death-inducing signaling complex.
Morgan, MJ; Kim, YS; Liu, ZG
Journal of immunology (Baltimore, Md. : 1950), 183(5):3278-3284, 2009
Journal of immunology (Baltimore, Md. : 1950)
The serine-threonine kinase RIP1 was originally identified through its ability to bind to the death domain of Fas (CD95). RIP1 has been shown to be recruited to the Fas death-inducing signaling complex (DISC) and is required for the induction of necrotic cell death. In this study, we show that in Jurkat T lymphocytes, RIP1 is also necessary for the most efficient activation of downstream caspases by Fas when treated with membrane-bound Fas ligand, but not with agonistic Abs or cross-linked soluble Fas ligand. RIP1 participates in the Fas-associated death domain protein-mediated recruitment of caspase-8 to the Fas receptor complex in a manner that promotes caspase-8 activation. Cross-linking Abs, such as CH11, bypass the requirement for RIP1 in caspase activation by initiating larger, though less efficient, DISC complexes, while membrane-bound Fas ligand initiates a smaller but more efficient DISC that functions, in part, by effectively incorporating more RIP1 into the complex. Consequently, RIP1 is likely a more integral part of physiological signaling through the Fas/CD95 receptor complex than previously recognized; at least when the signal is mediated by full-length membrane-bound FasL. Cross-linked soluble FasL, which also occurs physiologically, behaves similarly to the CH11 Ab, and may therefore be more likely to initiate nonapoptotic Fas signaling due to less RIP1 in the receptor complex. Thus, agonists that bind the same Fas receptor initiate mechanistically distinct pathways resulting in differential cytotoxicity.
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