GRANZYME-A IS AN INTERLEUKIN-1-BETA-CONVERTING ENZYME

Apoptosis is critically dependent on the presence of the ced-3 gene in Caenorhabditis elegans, which encodes a protein homologous to the mam malian interleukin (IL)-1 beta-converting enzyme (ICE). Overexpression of ICE or ced-3 promotes apoptosis. Cytotoxic T lymphocyte-mediated r apid apoptosis is induced by the proteases granzyme A and B. ICE and g ranzyme B share the rare substrate site of aspartic acid, after which amino acid cleavage of precursor IL-1 beta (pIL-1 beta) occurs. Here w e show that granzyme A, but not granzyme B, converts pIL-1 beta to its 17-kD mature form. Major cleavage occurs at Arg(120), four amino acid s downstream of the authentic processing site, Asp(116) IL-1 beta gene rated by granzyme A is biologically active. When pIL-1 beta processing is monitored in lipopolysaccharide-activated macrophage target cells attacked by cytotoxic T lymphocytes, intracellular conversion precedes lysis. Prior granzyme inactivation blocks this processing. We conclud e that the apoptosis-inducing granzyme A and ICE share at least one do wnstream target substrate, i.e., pIL-1 beta. This suggests that lympho cytes, by means of their own converting enzyme, could initiate a local inflammatory response independent of the presence of ICE.