TI - Differential requirements for caspase-8 activity in the mechanism of phosphorylation of eIF2alpha , cleavage of eIF4GI and signaling events associated with the inhibition of protein synthesis in apoptotic Jurkat T cells . AB - Previously we have reported that induction of apoptosis in Jurkat cells results in an inhibition of overall protein synthesis with the selective and rapid cleavage of eukaryotic initiation factor ( eIF ) 4GI . For the cleavage of eIF4GI , caspase-3 activity is both necessary and sufficient in vivo , in a process which does not require signaling through the p38 MAP kinase pathway . We now show that activation of the Fas/CD95 receptor promotes an early , transient increase in the level of eIF2alpha phosphorylation , which is temporally correlated with the onset of the inhibition of translation . This is associated with a modest increase in the autophosphorylation of the protein kinase activated by double-stranded RNA . Using a Jurkat cell line that is deficient in caspase-8 and resistant to anti-Fas -induced apoptosis , we show that whilst the cleavage of eIF4GI is caspase-8 -dependent , the enhancement of eIF2alpha phosphorylation does not require caspase-8 activity and occurs prior to the cleavage of eIF4GI . In addition , activation of the Fas/CD95 receptor results in the caspase-8 -dependent dephosphorylation and degradation of p70 (S6K) , the enhanced binding of 4E-BP1 to eIF4E , and , at later times , the cleavage of eIF2alpha . These data suggest that apoptosis impinges upon the activity of several polypeptides which are central to the regulation of protein synthesis and that multiple signaling pathways are involved in vivo .