Journal
EMBO JOURNAL
Volume 21, Issue 14, Pages 3704-3714Publisher
WILEY
DOI: 10.1093/emboj/cdf356
Keywords
apoptosis; caspase activation; caspase-8; CD95 (Fas/APO-1); c-FLIP
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Funding
- NIGMS NIH HHS [R01 GM061712, GM60911, R01 GM060911] Funding Source: Medline
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Activation of the caspase cascade is a pivotal step in apoptosis and can occur via death adaptor-mediated homo-oligomerization of initiator procaspases. Here we show that c-FLIPL, a protease-deficient caspase homolog widely regarded as an apoptosis inhibitor, is enriched in the CD95 death-inducing signaling complex (DISC) and potently promotes procaspase-8 activation through hetero-dimerization. c-FLIPL exerts its effect through its protease-like domain, which associates efficiently with the procaspase-8 protease domain and induces the enzymatic activity of the zymogen. Ectopic expression of c-FLIPL at physiologically relevant levels enhances procaspase-8 processing in the CD95 DISC and promotes apoptosis, while a decrease of c-FLIPL expression results in inhibition of apoptosis. c-FLIPL acts as an apoptosis inhibitor only at high ectopic expression levels. Thus, c-FLIPL defines a novel type of caspase regulator, distinct from the death adaptors, that can either promote or inhibit apoptosis.
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