Staufen1 promotes HCV replication by inhibiting protein kinase R and transporting viral RNA to the site of translation and replication in the cells.
Persistent hepatitis C virus (HCV) infection leads to chronic hepatitis C (CHC), which often progresses to liver cirrhosis (LC) and hepatocellular carcinoma (HCC). The molecular mechanisms that establish CHC and cause its subsequent development into LC and HCC are poorly understood. We have identified a cytoplasmic double-stranded RNA binding protein, Stau1, which is crucial for HCV replication. In this study, Stau1 specifically interacted with the variable-stem-loop region in the 3' NTR and domain IIId of the HCV-IRES in the 5' NTR, and promoted HCV replication and translation. Stau1 coimmunoprecipitates HCV NS5B and a cell factor, protein kinase R (PKR), which is critical for interferon-induced cellular antiviral and antiproliferative responses. Like Stau1, PKR displayed binding specificity to domain IIId of HCV-IRES. Stau1 binds to PKR and strongly inhibits PKR-autophosphorylation. We demonstrated that the transport of HCV RNA on the polysomes is Stau1-dependent, being mainly localized in the monosome fractions when Stau1 is downregulated and exclusively localized in the polysomes when Stau1 is overexpressed. Our findings suggest that HCV may appropriate Stau1 to its advantage to prevent PKR-mediated inhibition of eIF2α, which is required for the synthesis of HCV proteins for translocation of viral RNA genome to the polysomes for efficient translation and replication.
Department of Microbiology, Biochemistry and Molecular Genetics, New Jersey Medical School, Rutgers, Rutgers, the State University of New Jersey, 185 South Orange Avenue, Newark, NJ 07103, USA.
Updesh
U
Dixit
Department of Microbiology, Biochemistry and Molecular Genetics, New Jersey Medical School, Rutgers, Rutgers, the State University of New Jersey, 185 South Orange Avenue, Newark, NJ 07103, USA.
Ashutosh K
AK
Pandey
Department of Microbiology, Biochemistry and Molecular Genetics, New Jersey Medical School, Rutgers, Rutgers, the State University of New Jersey, 185 South Orange Avenue, Newark, NJ 07103, USA.
Priya
P
Mishra
Department of Microbiology, Biochemistry and Molecular Genetics, New Jersey Medical School, Rutgers, Rutgers, the State University of New Jersey, 185 South Orange Avenue, Newark, NJ 07103, USA.
Amitabha
A
Sengupta
Department of Microbiology, Biochemistry and Molecular Genetics, New Jersey Medical School, Rutgers, Rutgers, the State University of New Jersey, 185 South Orange Avenue, Newark, NJ 07103, USA vnp22@njms.rutgers.edu.
Virendra N
VN
Pandey
D001665:Binding Sites; D002460:Cell Line; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism*; D016679:Genome, Viral; D016174:Hepacivirus / Q000502:physiology*; D006526:Hepatitis C / Q000378:metabolism / Q000821:virology; D006801:Humans; D010766:Phosphorylation; D011132:Polyribosomes / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D014176:Protein Biosynthesis; D021381:Protein Transport; D034443:RNA Transport; D012367:RNA, Viral / Q000235:genetics* / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D020506:Untranslated Regions; D017361:Viral Nonstructural Proteins / Q000378:metabolism; D014779:Virus Replication; D019892:eIF-2 Kinase / Q000378:metabolism*; D012324:RNA-Dependent RNA Polymerase
D003598:Cytoskeletal Proteins; D012367:RNA, Viral; D016601:RNA-Binding Proteins; D020506:Untranslated Regions; D017361:Viral Nonstructural Proteins; D019892:eIF-2 Kinase; C492185:STAU1 protein, human; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase