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.
CITATION STYLE
Chang, D. W., Xing, Z., Pan, Y., Algeciras-Schimnich, A., Barnhart, B. C., Yaish-Ohad, S., … Yang, X. (2002). C-FLIPL is a dual function regulator for caspase-8 activation and CD95-mediated apoptosis. EMBO Journal, 21(14), 3704–3714. https://doi.org/10.1093/emboj/cdf356
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