期刊
MOLECULAR CELL
卷 61, 期 6, 页码 834-849出版社
CELL PRESS
DOI: 10.1016/j.molcel.2016.02.023
关键词
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资金
- UK Medical Research Council (MRC)
- Deutsche Forschungsgemeinschaft [RTG 2099]
- Medical Research Council [MC_U132685863] Funding Source: researchfish
- MRC [MC_U132685863] Funding Source: UKRI
The death-inducing signaling complex (DISC) initiates death receptor-induced apoptosis. DISC assembly and activation are controlled by c-FLIP isoforms, which function as pro-apoptotic (c-FLIPL only) or anti-apoptotic (c-FLIPL/c-FLIPS) regulators of procaspase-8 activation. Current models assume that c-FLIP directly competes with procaspase-8 for recruitment to FADD. Using a functional reconstituted DISC, structure-guided mutagenesis, and quantitative LC-MS/MS, weshowthat c-FLIPL/S binding to the DISC is instead a co-operative procaspase8- dependent process. FADD initially recruits procaspase- 8, which in turn recruits and heterodimerizes with c-FLIPL/S via a hierarchical binding mechanism. Procaspase-8 activation is regulated by the ratio of unbound c-FLIPL/S to procaspase-8, which determines composition of the procaspase-8: c-FLIPL/S heterodimer. Thus, procaspase-8: c-FLIPL exhibits localized enzymatic activity and is preferentially an activator, promoting DED-mediated procaspase-8 oligomer assembly, whereas procaspase-8: c-FLIPS lacks activity and potently blocks procaspase-8 activation. This co-operative hierarchical binding model explains the dual role of c-FLIPL and crucially defines how c-FLIP isoforms differentially control cell fate.
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