eIF2A mediates translation of hepatitis C viral mRNA under stress conditions

Abstract

Translation of most mRNAs is suppressed under stress conditions. Phosphorylation of the alpha-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 eIF2 alpha 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 eIF2 alpha phosphorylation by activating the eIF2 alpha 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-tRNAi to the P site of the 40S ribosomal subunit. The EMBO Journal (2011) 30, 2454-2464. doi: 10.1038/emboj.2011.146; Published online 10 May 2011