HETERONUCLEAR RIBONUCLEOPROTEINS C1 AND C2, COMPONENTS OF THE SPLICEOSOME, ARE SPECIFIC TARGETS OF INTERLEUKIN 1-BETA-CONVERTING ENZYME-LIKE PROTEASES IN APOPTOSIS

Apoptosis induced by a variety of agents results in the proteolytic cl eavage of a number of cellular substrates by enzymes related to interl eukin 1 beta-converting enzyme (ICE). A small number of substrates for these enzymes have been identified to date, including enzymes involve d in DNA repair processes: poly(ADP-ribose) polymerase and DNA-depende nt protein kinase. We describe here for the first time the specific cl eavage of the heteronuclear ribonucleoproteins (hnRNPs) C1 and C2 in a poptotic cells induced to undergo apoptosis by a variety of stimuli, i ncluding ionizing radiation, etoposide, and ceramide. No cleavage was observed in cells that are resistant to apoptosis induced by ionizing radiation. Protease inhibitor data implicate the involvement of an ICE -like protease in the cleavage of hnRNP C. Using recombinant ICE-like proteases and purified hnRNP C proteins in. vitro, we show that the C proteins are cleaved by Mch3 alpha and CPP32 and, to a lesser extent, by Mch2 alpha, but not by ICE, Nedd2, Tx, or the cytotoxic T-cell prot ease granzyme B. The results described here demonstrate that the hnRNP C proteins, abundant nuclear proteins thought to be involved in RNA s plicing, belong to a critical set of protein substrates that are cleav ed by ICE-like proteases during apoptosis.