c-FLIPL is a dual function regulator for caspase-8 activation and CD95-mediated apoptosis

Abstract

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.