Differential activation of interferon-inducible genes by hepatitis C virus core protein mediated by the interferon stimulated response element.
We previously found that hepatitis C virus (HCV) core protein, which possesses the consensus sequence of genotype 1b, transcriptionally activates the interferon (IFN)-inducible 2'-5'-oligoadenylate synthetase (2'-5'-OAS) gene in human hepatocyte cells. To clarify the mechanism of this activation, we further characterized the core protein as an activator of the 2'-5'-OAS gene. We demonstrated that the activation of the 2'-5'-OAS gene by the core protein is a general phenomenon, regardless of HCV genotype and strain. We showed that the 20 N-terminal amino acids (aa) of the core protein were important to the activation of the 2'-5'-OAS gene, although this N-terminal region did not have any effect on the subcellular localization of the core protein. We demonstrated that the core protein was able to activate all promoters possessing the IFN-stimulated response element (ISRE) examined. However, we found that the level of activation of the 2'-5'-OAS gene promoter possessing a particular variant type of ISRE was significantly higher than that of other IFN-inducible gene promoters. This phenomenon was confirmed using synthetic promoters possessing five repeats of the consensus or a 2'-5'-OAS-type ISRE. In addition, we showed that gene activation induced by the core protein is mediated by the ISRE. These results imply that the core protein prefers a subclass of IFN-inducible genes, the promoters of which possess the 2'-5'-OAS-type ISRE. Accordingly, we found that the IFN-inducible double-stranded RNA-specific adenosine deaminase gene promoter, possessing a 2'-5'-OAS-type ISRE sequence, was also efficiently activated by the core protein. The exact mechanism by which the core protein enhances gene expression was not determined, but we could find no effects of core protein on gene expression and phosphorylation status of the components of the JAK-STAT signaling transduction pathway.
Dansako
Hiromichi
H
Department of Molecular Biology, Okayama University Graduate School of Medicine and Dentistry, 2-5-1 Shikata-cho, Okayama 700-8558, Japan.
Naganuma
Atsushi
A
Nakamura
Takashi
T
Ikeda
Fusao
F
Nozaki
Akito
A
Kato
Nobuyuki
N
D015088:2',5'-Oligoadenylate Synthetase / Q000235:genetics*; D000243:Adenosine Deaminase / Q000096:biosynthesis / Q000235:genetics; D000595:Amino Acid Sequence; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000378:metabolism; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D049452:Green Fluorescent Proteins; D016174:Hepacivirus; D006801:Humans; D007372:Interferons / Q000502:physiology*; D053613:Janus Kinase 1; D008156:Luciferases / Q000032:analysis / Q000235:genetics; D008164:Luminescent Proteins / Q000378:metabolism; D008969:Molecular Sequence Data; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011506:Proteins / Q000378:metabolism; D016601:RNA-Binding Proteins; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D020218:Response Elements / Q000235:genetics*; D050794:STAT1 Transcription Factor; D050795:STAT2 Transcription Factor; D016415:Sequence Alignment; D015398:Signal Transduction; D053634:TYK2 Kinase; D015534:Trans-Activators / Q000378:metabolism; D015533:Transcriptional Activation; D014162:Transfection; D014758:Viral Core Proteins / Q000737:chemistry / Q000502:physiology*
D004268:DNA-Binding Proteins; D008164:Luminescent Proteins; D011506:Proteins; D016601:RNA-Binding Proteins; D011993:Recombinant Fusion Proteins; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050795:STAT2 Transcription Factor; D015534:Trans-Activators; D014758:Viral Core Proteins; C069130:nucleocapsid protein, Hepatitis C virus; D049452:Green Fluorescent Proteins; D007372:Interferons; D008156:Luciferases; D011505:Protein-Tyrosine Kinases; C507904:JAK1 protein, human; D053613:Janus Kinase 1; D053634:TYK2 Kinase; C070139:TYK2 protein, human; D015088:2',5'-Oligoadenylate Synthetase; C567955:ADARB1 protein, human; D000243:Adenosine Deaminase