Caspase-1 promiscuity is counterbalanced by rapid inactivation of the processed enzyme.

Abstract

Members of the caspase family of cysteine proteases coordinate the highly disparate processes of apoptosis and inflammation. However, while hundreds of substrates for the apoptosis effector caspases (caspase-3 and caspase-7) have been identified, only two confirmed substrates for the key inflammatory protease (caspase-1) are known. Whether this reflects intrinsic differences in the substrate specificity of inflammatory versus apoptotic caspases, or their relative abundance in vivo, is unknown. To address this issue, we have compared the specificity of caspases-1, -3 and -7 towards peptide and protein substrates. Contrary to expectation, caspase-1 displayed concentration-dependent promiscuity towards a variety of substrates, suggesting that caspase-1 specificity is maintained by restricting its abundance. While endogenous concentrations of caspase-1 were found to be similar to caspase-3, processed caspase-1 was found to be much more labile, with a half-life of approximately 9 minutes. This contrasted sharply with the active forms of caspase-3 and caspase-7, which exhibited half-lives of 8 and 11 h respectively. We propose that the high degree of substrate specificity displayed by caspase-1 is maintained through rapid spontaneous inactivation of this protease.