Fas-activated Ser/Thr phosphoprotein (FAST) is a eukaryotic initiation factor 4E-binding protein that regulates mRNA stability and cell survival

Abstract

The recognition of T cell intracellular antigen-1 (TIA-1) by Fas-activated Ser/Thr phosphoprotein (FAST) results in prolonged cell survival by inducing the expression of inhibitors of apoptosis. Here we show that the functional effects of FAST are dependent on its interactions with eukaryotic translation initiation factor 4E (eIF4E) which is the major cytosolic cap binding protein in cells. FAST binds to eIF4E via a consensus motif (428YXXXXLL433) that is also found in eIF4G, 4E-BP1/2/3, 4E-T, and cup. A point mutation within this motif at Y428 dampens the ability of FAST to recognize eIF4E. Wild-type (WT) FAST, but not its Y428G mutant, increases the expression of co-transfected cellular inhibitor of apoptosis-1 (cIAP-1) and β-gal mRNA and protein, but inhibits the Fas-induced activation of caspase-3. Increased expression of the co-transfected proteins results, in part, from stabilization of mRNA, suggesting that FAST:eIF4E interactions can inhibit mRNA decay. We propose that eIF4E:FAST:TIA-1 complexes regulate the translation and stability of specific mRNAs that encode proteins important for cell survival.