Identification of Ipaf, a human caspase-1-activating protein related to Apaf-1

Procaspase-9 contains an NH2-terminal caspase-associated recruitment domain (CARD), which is essential for direct association with Apaf-1 and activati on. Procaspase-1 also contains an NH2-terminal CARD domain, suggesting that its mechanism of activation, like that of procaspase-9, involves associati on with an Apaf-1-related molecule. Here we describe the identification of a human Apaf-1-related protein, named Ipaf that contains an NH2-terminal CA RD domain, a central nucleotide-binding domain, and a COOH-terminal regulat ory leucine-rich repeat domain (LRR). Ipaf associates directly and specific ally with the CARD domain of procaspase-1 through CARD-CARD interaction. A constitutively active Ipaf lacking its COOH-terminal LRR domain can induce autocatalytic processing and activation of procaspase-1 and caspase-1-depen dent apoptosis in transfected cells. Our results suggest that Ipaf is a spe cific and direct activator of procaspase-1 and could be involved in activat ion of caspase-1 in response to pro-inflammatory and apoptotic stimuli.