title: Caspase-1 promiscuity is counterbalanced by rapid inactivation of processed enzyme.
abstract: Members of the caspase family of cysteine proteases coordinate the highly disparate processes of apoptosis and inflammation. However, although 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 toward peptide and protein substrates. Contrary to expectation, caspase-1 displayed concentration-dependent promiscuity toward a variety of substrates, suggesting that caspase-1 specificity is maintained by restricting its abundance. Although 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 ~9 min. 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.
authors.affiliation: Molecular Cell Biology Laboratory, Department of Genetics, The Smurfit Institute, Trinity College, Dublin 2, Ireland.
authors.forename: John G
authors.initials: JG
authors.lastname: Walsh
authors.forename: Susan E
authors.initials: SE
authors.lastname: Logue
authors.forename: Alexander U
authors.initials: AU
authors.lastname: Lüthi
authors.forename: Seamus J
authors.initials: SJ
authors.lastname: Martin
mesh_terms: D020170:Caspase 1 / Q000235:genetics / Q000378:metabolism*; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D053179:Caspase 7 / Q000235:genetics / Q000378:metabolism; D004795:Enzyme Stability / Q000502:physiology; D006801:Humans; D019169:Jurkat Cells; D013379:Substrate Specificity / Q000502:physiology
chemical_list: C505407:CASP3 protein, human; C505520:CASP7 protein, human; D053148:Caspase 3; D053179:Caspase 7; D020170:Caspase 1