151. Hepatitis C Virus NS5A Binds to the mRNA Cap-binding Eukaryotic Translation Initiation 4F (eIF4F) Complex and Up-regulates Host Translation Initiation Machinery through eIF4E-binding Protein 1 Inactivation
- Author
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Anju George, Devika Kudmulwar, Harinivas Harshan Krishnan, Swarupa Panda, Sanjeev Chavan Nayak, and Salma Pathan Chhatbar
- Subjects
Carcinoma, Hepatocellular ,viruses ,Eukaryotic Initiation Factor-4E ,Drug Resistance ,Cell Cycle Proteins ,Hepacivirus ,Mechanistic Target of Rapamycin Complex 1 ,Viral Nonstructural Proteins ,Biology ,Microbiology ,Biochemistry ,Eukaryotic initiation factor 4F ,Cell Line, Tumor ,Eukaryotic initiation factor ,Humans ,Initiation factor ,Phosphorylation ,Peptide Chain Initiation, Translational ,Molecular Biology ,Adaptor Proteins, Signal Transducing ,Sirolimus ,TOR Serine-Threonine Kinases ,Liver Neoplasms ,EIF4E ,Proteins ,Ribosomal Protein S6 Kinases, 70-kDa ,virus diseases ,Cell Biology ,EIF4A1 ,biochemical phenomena, metabolism, and nutrition ,Cell Transformation, Viral ,Phosphoproteins ,Hepatitis C ,digestive system diseases ,Eukaryotic translation initiation factor 4 gamma ,Anti-Bacterial Agents ,Up-Regulation ,Cell biology ,EIF4EBP1 ,Eukaryotic Initiation Factor-4F ,Multiprotein Complexes ,Polyribosomes ,biological phenomena, cell phenomena, and immunity ,Transcription Factors - Abstract
Initiation, a major rate-limiting step of host protein translation, is a critical target in many viral infections. Chronic hepatitis C virus (HCV) infection results in hepatocellular carcinoma. Translation initiation, up-regulated in many cancers, plays a critical role in tumorigenesis. mTOR is a major regulator of host protein translation. Even though activation of PI3K-AKT-mTOR by HCV non-structural protein 5A (NS5A) is known, not much is understood about the regulation of host translation initiation by this virus. Here for the first time we show that HCV up-regulates host cap-dependent translation machinery in Huh7.5 cells through simultaneous activation of mTORC1 and eukaryotic translation initiation factor 4E (eIF4E) by NS5A. NS5A, interestingly, overexpressed and subsequently hyperphosphorylated 4EBP1. NS5A phosphorylated eIF4E through the p38 MAPK-MNK pathway. Both HCV infection and NS5A expression augmented eIF4F complex assembly, an indicator of cap-dependent translation efficiency. Global translation, however, was not altered by HCV NS5A. 4EBP1 phosphorylation, but not that of S6K1, was uniquely resistant to rapamycin in NS5A-Huh7.5 cells, indicative of an alternate phosphorylation mechanism of 4EBP1. Resistance of Ser-473, but not Thr-308, phosphorylation of AKT to PI3K inhibitors suggested an activation of mTORC2 by NS5A. NS5A associated with eIF4F complex and polysomes, suggesting its active involvement in host translation. This is the first report that implicates an HCV protein in the up-regulation of host translation initiation apparatus through concomitant regulation of multiple pathways. Because both mTORC1 activation and eIF4E phosphorylation are involved in tumorigenesis, we propose that their simultaneous activation by NS5A might contribute significantly to the development of hepatocellular carcinoma.
- Published
- 2012