CrmA-inhibitable cleavage of the 70-kDa protein component of the U1 small nuclear ribonucleoprotein during Fas- 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 than can inhibit interleukin-1 beta converting enzyme (ICE) and ICE-like proteases. We showed previously that expression of CrmA potently blocks apoptosis induced by activation of either Fas or TNF-R, implicating 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 proteolytic substrate rapidly cleaved during both Fas- and TNF-R-induced apoptosis. This cleavage was inhibited by expression of CrmA, but not by expression of an inactive point mutant of CrmA, confirming the involvement of an ICE-like protease. These data for the first time identify U1-70 kDa as a death substrate cleaved during Fas- and TNF-R-induced apoptosis and emphasize the importance of protease activation in the cell death pathway.
Tewari
M
M
Department of Pathology, University of Michigan Medical School, Ann Arbor 48109, USA.
Beidler
D R
DR
Dixit
V M
VM
D000954:Antigens, Surface / Q000502:physiology*; D017209:Apoptosis; D006801:Humans; D008970:Molecular Weight; D018124:Receptors, Tumor Necrosis Factor / Q000502:physiology; D017412:Ribonucleoprotein, U1 Small Nuclear / Q000378:metabolism*; D015843:Serpins / Q000502:physiology*; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D014764:Viral Proteins; D019014:fas Receptor
D000954:Antigens, Surface; D018124:Receptors, Tumor Necrosis Factor; D017412:Ribonucleoprotein, U1 Small Nuclear; D015843:Serpins; D014409:Tumor Necrosis Factor-alpha; D014764:Viral Proteins; D019014:fas Receptor; C074641:interleukin-1beta-converting enzyme inhibitor