I-FLICE, a novel inhibitor of tumor necrosis factor receptor-1- and CD- 95-induced apoptosis

Abstract

The pivotal discovery that the death proteases caspase 8 (FLICE) and caspase 10 (Mch4/FLICE2) are recruited to the CD-95 and tumor necrosis factor receptor-1 signaling complexes suggested a mechanism used by these cytotoxic receptors to initiate apoptosis. In this report, we describe the cloning and characterization of I-FLICE, a novel inhibitor of tumor necrosis factor receptor-1- and CD-95-induced apoptosis. The overall architecture of I-FLICE is strikingly similar to that of FLICE and Mch4/FLICE2. However, I-FLICE lacks both a catalytic active site and residues that form the substrate binding pocket, in keeping with its dominant negative inhibitory function. I- FLICE is the first example of a catalytically inert caspase that can inhibit apoptosis.