CASPASE-4 AND CASPASE-5, MEMBERS OF THE ICE CED-3 FAMILY OF CYSTEINE PROTEASES, ARE CRMA-INHIBITABLE PROTEASES/

Proteases of the caspase family are implicated in mammalian apoptosis and constitute a protease cascade. We characterized caspase-4 (TX/ICH- 2/ICErelII) and caspase-5 (ICErelIII/TY), which are most closely relat ed to caspase-1 (ICE) among the caspase family. Although overexpressio n of caspase-4 and caspase-5 induced apoptosis, confirming previous ob servations, this apoptosis was not inhibited by a caspase-1-specific t etrapeptide inhibitor (Ac-YVAD-CHO), suggesting that caspase-4 and cas pase-5 have different substrate specificities from caspase-1 and also that caspase-4- and caspase-5-induced apoptosis is not mediated by cas pase-1. CrmA, a cowpox virus-derived caspase-1 inhibitor that prevents apoptosis induced by various stimuli, was cleaved by caspase-4 and ca spase-5, and inhibited their proteolytic activity as assessed by cleav age of pro-caspase-3 (pro-CPP32/Yama/apopain). Thus, caspase-4 and cas pase-5 are CrmA-inhibitable proteases like caspase-1 and might be invo lved in apoptosis.