title: eIF2A mediates translation of hepatitis C viral mRNA under stress conditions.
abstract: Translation of most mRNAs is suppressed under stress conditions. Phosphorylation of the α-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 eIF2α 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 eIF2α phosphorylation by activating the eIF2α 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.
authors.affiliation: Department of Life Science, POSTECH Biotech Center, Pohang University of Science and Technology, Pohang, Korea.
authors.forename: Joon Hyun
authors.initials: JH
authors.lastname: Kim
authors.forename: Sung Mi
authors.initials: SM
authors.lastname: Park
authors.forename: Ji Hoon
authors.initials: JH
authors.lastname: Park
authors.forename: Sun Ju
authors.initials: SJ
authors.lastname: Keum
authors.forename: Sung Key
authors.initials: SK
authors.lastname: Jang
mesh_terms: D045744:Cell Line, Tumor; D015852:Eukaryotic Initiation Factor-2 / Q000502:physiology*; D006367:HeLa Cells; D016174:Hepacivirus / Q000235:genetics* / Q000378:metabolism*; D006526:Hepatitis C / Q000235:genetics / Q000378:metabolism; D006801:Humans; D016254:Mutagenesis, Insertional; D014176:Protein Biosynthesis / Q000235:genetics*; D054730:Protein Interaction Domains and Motifs / Q000235:genetics; D025941:Protein Interaction Mapping / Q000379:methods; D012333:RNA, Messenger / Q000235:genetics* / Q000378:metabolism; D012367:RNA, Viral / Q000235:genetics* / Q000378:metabolism; D054682:Ribosome Subunits, Small, Eukaryotic / Q000235:genetics / Q000378:metabolism; D013312:Stress, Physiological / Q000235:genetics*
chemical_list: D015852:Eukaryotic Initiation Factor-2; D012333:RNA, Messenger; D012367:RNA, Viral