Cooperation and constraint: the complex association of caspase-8 and cFLIP

Abstract

Abstract

Caspases exert their function by cleaving proteins, primarily self-cleavage as part of their maturation in cell death signaling complexes, and cleavage of other caspases to engage downstream cell death signaling pathways. Caspase-8 has a unique place in cell death decisions because it can both promote apoptosis and prevent necroptosis (Fig. 1 ), thereby engaging opposing pro-and anti-inflammatory pathways [ 1 ]. Mechanistically-speaking, these opposing outcomes depend on interaction with the adaptor protein FADD (Fas-Associated Death Domain protein), dimerization state and self-cleavage. Downstream from recognition of death ligands by their cognate receptors, including Fas and TNFR1 (Tumor Necrosis Factor Receptor 1), latent caspase-8 is activated by dimerization via recruitment to the oligomeric platform known as the death inducing signaling complex (DISC). Once activated, a caspase-8 homodimer can cleave itself at position Asp387 in mouse, or Asp374 or Asp384 in human. This processing event splits the catalytic domain into two subunits, resulting in a more active and stable conformation that is crucial for its proapoptotic function in the context of homodimerization [ 2 ]. Adjacent to the Casp8 genetic locus is the gene encoding the pseudocaspase cFLIP (Cellular FLICE-like Inhibitory Protein), Cflar . A variant of this protein (cFLIP L ) contains the same protein fold as caspase-8 but lacks the catalytic residues. Increased concentration of cFLIP L favor the formation of caspase-8/cFLIP L heterodimers, which inhibit caspase-8 proapoptotic function but can promote its anti-necroptotic function [ 3 ]. When caspase-8 partners with cFLIP L , intersubunit linker proteolysis is not required. In vitro, the heterodimer is an attenuated enzyme [ 4 ]. Thus, cFLIP L can activate caspase-8 by dimerization to generate a heterodimer with different substrate specificity than the homodimeric caspase-8, which has an apoptotic role. Fig. 1 Full size image Cell death pathways influenced by the dimerization state of caspase-8.