eIF2A mediates translation of hepatitis C viral mRNA under stress conditions
- 10 May 2011
- journal article
- Published by Springer Science and Business Media LLC in The EMBO Journal
- Vol. 30 (12), 2454-2464
- https://doi.org/10.1038/emboj.2011.146
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‐tRNAi) 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‐tRNAi 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‐tRNAi to the P site of the 40S ribosomal subunit.Keywords
This publication has 56 references indexed in Scilit:
- Activities of Ligatin and MCT-1/DENR in eukaryotic translation initiation and ribosomal recyclingGenes & Development, 2010
- GTP-independent tRNA Delivery to the Ribosomal P-site by a Novel Eukaryotic Translation FactorOnline Journal of Public Health Informatics, 2010
- The mechanism of eukaryotic translation initiation and principles of its regulationNature Reviews Molecular Cell Biology, 2010
- Hepatitis C Virus Blocks Interferon Effector Function by Inducing Protein Kinase R PhosphorylationCell Host & Microbe, 2009
- Structure and function of HCV IRES domainsVirus Research, 2009
- RNA-Binding Protein hnRNP D Modulates Internal Ribosome Entry Site-Dependent Translation of Hepatitis C Virus RNAJournal of Virology, 2008
- eIF2-dependent and eIF2-independent modes of initiation on the CSFV IRES: a common role of domain IIThe EMBO Journal, 2008
- Monitoring the Antiviral Effect of Alpha Interferon on Individual CellsJournal of Virology, 2007
- Initiation of Protein Synthesis by Hepatitis C Virus Is Refractory to Reduced eIF2 · GTP · Met-tRNAiMetTernary Complex AvailabilityMolecular Biology of the Cell, 2006
- Production of infectious hepatitis C virus in tissue culture from a cloned viral genomeNature Medicine, 2005