title: HCV NS5A co-operates with PKR in modulating HCV IRES-dependent translation.
abstract: Translation initiation of the Hepatitis C virus (HCV) genome is driven by an internal ribosome entry site (IRES), located within the 5' non-coding region. Several studies have suggested that different cellular non canonical proteins or viral proteins can regulate the HCV IRES activity. However, the role of the viral proteins on HCV translation remains controversial. In this report, we confirmed previous studies showing that NS5A down-regulates IRES activity in HepG2 but not in Huh7 cells suggesting that the NS5A effect on HCV IRES is cell-type dependent. Additionally, we provide strong evidence that activated PKR up-regulates the IRES activity while silencing of endogenous PKR had the opposite effect. Furthermore, we present data indicating that the NS5A-mediated inhibitory effect on IRES-dependent translation could be linked with the PKR inactivation. Finally, we show that NS5A from GBV-C but not from GBV-B down-regulates HCV IRES activity in the absence or the presence of PKR over expression. Notably, HCV and GBV-C but not GBV-B NS5A contains a previously identified PKR interacting protein domain.
authors.affiliation: Molecular Virology Laboratory, Hellenic Pasteur Institute, Athens, Greece; University of Patras, School of Health Sciences, Department of Pharmacy, Greece.
authors.forename: Eirini
authors.initials: E
authors.lastname: Karamichali
authors.affiliation: Molecular Virology Laboratory, Hellenic Pasteur Institute, Athens, Greece.
authors.forename: Pelagia
authors.initials: P
authors.lastname: Foka
authors.affiliation: Molecular Virology Laboratory, Hellenic Pasteur Institute, Athens, Greece.
authors.forename: Eliza
authors.initials: E
authors.lastname: Tsitoura
authors.affiliation: Molecular Virology Laboratory, Hellenic Pasteur Institute, Athens, Greece.
authors.forename: Katerina
authors.initials: K
authors.lastname: Kalliampakou
authors.affiliation: Molecular Virology Laboratory, Hellenic Pasteur Institute, Athens, Greece.
authors.forename: Dorothea
authors.initials: D
authors.lastname: Kazazi
authors.affiliation: Molecular Virology/Microbiology, University of Nicosia Medical School, Cyprus.
authors.forename: Peter
authors.initials: P
authors.lastname: Karayiannis
authors.affiliation: Molecular Virology Laboratory, Hellenic Pasteur Institute, Athens, Greece.
authors.forename: Urania
authors.initials: U
authors.lastname: Georgopoulou
authors.affiliation: Molecular Virology Laboratory, Hellenic Pasteur Institute, Athens, Greece. Electronic address: penelopm@pasteur.gr.
authors.forename: Penelope
authors.initials: P
authors.lastname: Mavromara
mesh_terms: D020121:5' Untranslated Regions; D000595:Amino Acid Sequence; D004789:Enzyme Activation; D029407:GB virus C / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D015967:Gene Expression Regulation, Viral; D056945:Hep G2 Cells; D016174:Hepacivirus / Q000235:genetics* / Q000378:metabolism*; D006526:Hepatitis C / Q000235:genetics / Q000378:metabolism / Q000821:virology; D006801:Humans; D008969:Molecular Sequence Data; D011485:Protein Binding; D014176:Protein Biosynthesis; D054730:Protein Interaction Domains and Motifs; D016415:Sequence Alignment; D017361:Viral Nonstructural Proteins / Q000737:chemistry / Q000378:metabolism*; D019892:eIF-2 Kinase / Q000235:genetics / Q000378:metabolism*; D012324:RNA-Dependent RNA Polymerase
chemical_list: D020121:5' Untranslated Regions; D017361:Viral Nonstructural Proteins; D019892:eIF-2 Kinase; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase
keywords: GBV-B NS5A; GBV-C NS5A; HCV IRES; HCV NS5A; PKR; Translation