title: Hepatitis B virus polymerase inhibits the interferon-inducible MyD88 promoter by blocking nuclear translocation of Stat1.
abstract: Previous studies have suggested that hepatitis B virus (HBV) blocks expression of the alpha interferon (IFN-alpha)-inducible myeloid differential primary response protein (MyD88) gene. To study the molecular mechanism(s) of the inhibition of MyD88 expression by HBV, MyD88 promoter reporter plasmids and vectors expressing different HBV viral proteins were constructed. Co-transfection experiments showed that IFN-induced MyD88 promoter activity was inhibited by HBV polymerase expression in a dose-dependent manner and that the terminal protein (TP) domain of HBV polymerase was responsible for this antagonistic activity. Analysis of site mutants showed that the region targeted by the polymerase protein contained the signal transducer and activator of transcription (Stat) binding site. Chromatin immunoprecipitation analysis showed that the IFN-induced DNA-binding activity of Stat1 was affected. Further study demonstrated that the HBV polymerase protein inhibited the Stat1 nuclear translocation induced by IFN-alpha, but did not induce Stat1 degradation nor interfere with its phosphorylation. In addition, HBV polymerase could inhibit the transcriptional activity of other IFN-stimulated response element-driven promoters and the expression of interferon-stimulated genes (ISGs), such as Stat1 and ISG15. In summary, these results indicate that HBV polymerase is a general inhibitor of IFN signalling and can inhibit IFN-inducible MyD88 expression by inhibiting the activity of the MyD88 promoter through blocking the nuclear translocation of Stat1.
authors.affiliation: Department of Research, Shanghai Public Health Clinic Center, Fudan University, Shanghai 201508, China.|Key Laboratory of Medical Molecular Virology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
authors.forename: Min
authors.initials: M
authors.lastname: Wu
authors.affiliation: Key Laboratory of Medical Molecular Virology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Institutes of Medical Microbiology and Biomedical Sciences, Fudan University, Shanghai 200032, China.|Key Laboratory of Medical Molecular Virology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
authors.forename: Shanshan
authors.initials: S
authors.lastname: Lin
authors.affiliation: Department of Research, Shanghai Public Health Clinic Center, Fudan University, Shanghai 201508, China.
authors.forename: Xiaonan
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Medical Molecular Virology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
authors.forename: Li
authors.initials: L
authors.lastname: Xiang
authors.affiliation: Institutes of Medical Microbiology and Biomedical Sciences, Fudan University, Shanghai 200032, China.|Department of Research, Shanghai Public Health Clinic Center, Fudan University, Shanghai 201508, China.|Key Laboratory of Medical Molecular Virology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
authors.forename: Zhenghong
authors.initials: Z
authors.lastname: Yuan
mesh_terms: D001483:Base Sequence; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D004259:DNA-Directed DNA Polymerase / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D015967:Gene Expression Regulation, Viral; D006509:Hepatitis B / Q000378:metabolism / Q000821:virology*; D006515:Hepatitis B virus / Q000502:physiology*; D006801:Humans; D016898:Interferon-alpha / Q000378:metabolism / Q000494:pharmacology; D007372:Interferons / Q000378:metabolism*; D008969:Molecular Sequence Data; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D050794:STAT1 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D014764:Viral Proteins / Q000502:physiology*
chemical_list: D016898:Interferon-alpha; C507779:MYD88 protein, human; D053594:Myeloid Differentiation Factor 88; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D014764:Viral Proteins; D007372:Interferons; D004259:DNA-Directed DNA Polymerase