Proteasome inhibitors and immunosuppressive drugs promote the cleavage of eIF4GI and eIF4GII by caspase-8-independent mechanisms in Jurkat T cell lines

Previously, we have shown that translation eukaryotic initiation factor (eI F) 4GI is cleaved during anti-Fas-mediated apoptosis. Here, we have investi gated the effects of the proteasome inhibitors, MG132 and lactacystin, and the immunosuppressants, 2-amino -2 [2-(4-octylphenyl) ethyl] -1,3, propane diol (FTY720) and cyclosporin A, on the integrity of eIF4GI and eIF4GII in T cells. Using wild-type Jurkat T cells, we show that the proteasome inhibi tors MG132 and lactacystin promote the cleavage of eIF4G, activate caspase- 8 and caspase-3-like activities and decrease cell viability. Furthermore, M G132 also promotes the cleavage of eIF4G and the activation of caspase-3-li ke activity in a caspase-8-deficient Jurkat cell line which is resistant to anti-Fas-mediated apoptosis. Using specific anti-peptide antisera, we show that both eIF4GI and eIF4GII are cleaved in either cell line in response t o MG132 and lactacystin. In response to such treatments, we demonstrate tha t the fragments of eIF4GI generated include those previously observed with anti-Fas antiserum together with a novel product which lacks the ability to interact with eIF4E. In contrast, cells treated with the immunosuppressant s FTY720 and cyclosporin A appear to contain only the novel cleavage fragme nt of eIF4GI and to lack those characteristic of cells treated with anti-Fa s antiserum. These data suggest that caspase-8 activation is not required f or apoptosis and eIF4G cleavage mediated by proteasome inhibitors and immun osuppress ants in human T cells. (C) 2001 Federation of European Biochemica l Societies. Published by Elsevier Science B.V. All rights reserved.