CRMA-INHIBITABLE CLEAVAGE OF THE 70-KDA PROTEIN-COMPONENT OF THE U1 SMALL NUCLEAR RIBONUCLEOPROTEIN DURING FAS-INDUCED AND TUMOR NECROSIS FACTOR-INDUCED APOPTOSIS

Fas and the type I tumor necrosis factor receptor (TNF-R) are two cell surface receptors that, when stimulated with ligand or cross-linking antibody, trigger apoptotic cell death by a mechanism that has yet to be elucidated, The CrmA protein is a serpin family protease inhibitor that can inhibit interleukin-1 beta converting enzyme (ICE) and ICE-Li ke proteases. We showed previously that expression of CrmA potently bl ocks apoptosis induced by activation of either Fas or TNF-R, implicati ng protease involvement in these death pathways (Tewari, M., and Dixit , V. M. (1995) J. Biol. Chem. 270, 3255-3260). Here we report that the 70-kDa component of the U1 small ribonucleoprotein (U1-70 kDa) is a p roteolytic substrate rapidly cleaved during both Fas- and TNF-R-induce d apoptosis, This cleavage was inhibited by expression of CrmA but not by expression of an inactive point mutant of CrmA, confirming the inv olvement of an ICE-like protease, These data for the first time identi fy U1-70 kDa as a death substrate cleaved during Fas- and TNF-R-induce d apoptosis and emphasize the importance of protease activation in the cell death pathway.