title: Increased expression of Gp96 by HBx-induced NF-κB activation feedback enhances hepatitis B virus production.
abstract: Elevated expression of heat shock protein gp96 in hepatitis B virus (HBV)-infected patients is positively correlated with the progress of HBV-induced diseases, but little is known regarding the molecular mechanism of virus-induced gp96 expression and its impact on HBV infection. In this study, up-regulation of gp96 by HBV replication was confirmed both in vitro and in vivo. Among HBV components, HBV x protein (HBx) was found to increase gp96 promoter activity and enhance gp96 expression by using a luciferase reporter system, and western blot analysis. Further, we found that HBx-mediated regulation of gp96 expression requires a NF-κB cis-regulatory element on the gp96 promoter, and chromatin immunoprecipitation results demonstrated that HBx promotes the binding of NF-κB to the gp96 promoter. Significantly, both gain- and loss-of-function studies showed that gp96 enhances HBV production in HBV-transfected cells and a mouse model based on hydrodynamic transfection. Moreover, up-regulated gp96 expression was observed in HBV-infected patients, and gp96 levels were correlated with serum viral loads. Thus, our work demonstrates a positive feedback regulatory pathway involving gp96 and HBV, which may contribute to persistent HBV infection. Our data also indicate that modulation of gp96 function may represent a novel strategy for the intervention of HBV infection.
authors.affiliation: CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, China.
authors.forename: Hongxia
authors.initials: H
authors.lastname: Fan
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Yan
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhang
authors.forename: Xiaojun
authors.initials: X
authors.lastname: Zhang
authors.forename: Yanzhou
authors.initials: Y
authors.lastname: Gao
authors.forename: Yaxing
authors.initials: Y
authors.lastname: Xu
authors.forename: Fusheng
authors.initials: F
authors.lastname: Wang
authors.forename: Songdong
authors.initials: S
authors.lastname: Meng
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D002460:Cell Line; D047369:Chromatin Immunoprecipitation; D005260:Female; D005786:Gene Expression Regulation; D006515:Hepatitis B virus / Q000235:genetics / Q000378:metabolism / Q000472:pathogenicity / Q000502:physiology*; D006801:Humans; D008297:Male; D051379:Mice; D008875:Middle Aged; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism*; D054334:Viral Regulatory and Accessory Proteins; D014779:Virus Replication / Q000502:physiology*; D055815:Young Adult
chemical_list: D016328:NF-kappa B; D015534:Trans-Activators; D014764:Viral Proteins; D054334:Viral Regulatory and Accessory Proteins; C057628:hepatitis B virus X protein