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PLoS One. 2013 Jun 11;8(6):e65588. doi: 10.1371/journal.pone.0065588. Print 2013.

Increased expression of Gp96 by HBx-induced NF-κB activation feedback enhances hepatitis B virus production.

Author information

  • 1CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, China.

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.

PMID:
23776506
[PubMed - indexed for MEDLINE]
PMCID:
PMC3679196
Free PMC Article

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