EIF2A mediates translation of hepatitis C viral mRNA under stress conditions

Abstract

Translation of most mRNAs is suppressed under stress conditions. Phosphorylation of the Î ±-subunit of eukaryotic translation initiation factor 2 (eIF2), which delivers initiator tRNA (Met-tRNA i) to the P site of the 40S ribosomal subunit, is responsible for such translational suppression. However, translation of hepatitis C viral (HCV) mRNA is refractory to the inhibitory effects of eIF2Î ± phosphorylation, which prevents translation by disrupting formation of the eIF2-GTP-Met-tRNA i ternary complex. Here, we report that eIF2A, an alternative initiator tRNA-binding protein, has a key role in the translation of HCV mRNA during HCV infection, in turn promoting eIF2Î ± phosphorylation by activating the eIF2Î ± kinase PKR. Direct interaction of eIF2A with the IIId domain of the HCV internal ribosome entry site (IRES) is required for eIF2A-dependent translation. These data indicate that stress-independent translation of HCV mRNA occurs by recruitment of eIF2A to the HCV IRES via direct interaction with the IIId domain and subsequent loading of Met-tRNA i to the P site of the 40S ribosomal subunit. © 2011 European Molecular Biology Organization | All Rights Reserved.