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 related to Caspase-1 (ICE) among the Caspase family. Although overexpression of caspase-4 and caspase-5 induced Apoptosis, confirming previous observations, this Apoptosis was not inhibited by a caspase-1-specific tetrapeptide inhibitor (Ac-YVAD-CHO), suggesting that caspase-4 and caspase-5 have different substrate specificities from Caspase-1 and also that caspase-4- and caspase-5-induced Apoptosis is not mediated by Caspase-1. CrmA, a cowpox virus-derived Caspase-1 inhibitor that prevents Apoptosis induced by various stimuli, was cleaved by caspase-4 and caspase-5, and inhibited their proteolytic activity as assessed by cleavage of pro-caspase-3 (pro-CPP32/Yama/apopain). Thus, caspase-4 and caspase-5 are CrmA-inhibitable proteases like Caspase-1 and might be involved in Apoptosis.