Krüppel-like factor 15 activates hepatitis B virus gene expression and replication

Authors

  • Jie Zhou,

    1. Department of Pathology, University of California San Francisco, San Francisco, CA
    2. Pathology Service 113B, Veterans Affairs (VA) Medical Center, San Francisco, CA
    Current affiliation:
    1. Department of Microbiology, The University of Hong Kong, Hong Kong, China; Current address for Thomas Tan: CytoDesign, Inc., Sunnyvale, CA
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    • These authors contributed equally to this work.

  • Thomas Tan,

    1. Department of Pathology, University of California San Francisco, San Francisco, CA
    2. Pathology Service 113B, Veterans Affairs (VA) Medical Center, San Francisco, CA
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    • These authors contributed equally to this work.

  • Yongjun Tian,

    1. Department of Molecular Microbiology and Immunology, University of Southern California, Los Angeles, CA
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  • Bojian Zheng,

    1. Department of Microbiology, The University of Hong Kong, Hong Kong, China
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  • J.-H. James Ou,

    1. Department of Molecular Microbiology and Immunology, University of Southern California, Los Angeles, CA
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  • Eric J. Huang,

    Corresponding author
    1. Department of Pathology, University of California San Francisco, San Francisco, CA
    2. Pathology Service 113B, Veterans Affairs (VA) Medical Center, San Francisco, CA
    • Department of Pathology, UCSF and Pathology Service 113B, VA Medical Center, San Francisco, CA 94121
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    • fax: 415-750-6947

  • T.S. Benedict Yen

    1. Department of Pathology, University of California San Francisco, San Francisco, CA
    2. Pathology Service 113B, Veterans Affairs (VA) Medical Center, San Francisco, CA
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  • Potential conflict of interest: Nothing to report.

  • This work was supported by National Institutes of Health grants R01CA55578 (to T.S.B.Y.), R21RR024229 (to T.S.B.Y.), and P01CA123328 (to T.S.B.Y. and J.H.J.O.), a VA Merit Review Award (to T.S.B.Y.), and an American Cancer Society postdoctoral fellowship (to T.T.).

Abstract

Hepatitis B virus (HBV) is a small DNA virus that requires cellular transcription factors for the expression of its genes. To understand the molecular mechanisms that regulate HBV gene expression, we conducted a yeast one-hybrid screen to identify novel cellular transcription factors that may control HBV gene expression. Here, we demonstrate that Krüppel-like factor 15 (KLF15), a liver-enriched transcription factor, can robustly activate HBV surface and core promoters. Mutations in the putative KLF15 binding site in the HBV core promoter abolished the ability of KLF15 to activate the core promoter in luciferase assays. Furthermore, the overexpression of KLF15 stimulated the expression of HBV surface antigen (HBsAg) and the core protein and enhanced viral replication. Conversely, small interfering RNA knockdown of the endogenous KLF15 in Huh7 cells resulted in a reduction in HBV surface- and core-promoter activities. In electrophoretic mobility shift and chromatin immunoprecipitation assays, KLF15 binds to DNA probes derived from the core promoter and the surface promoter. Introduction of an expression vector for KLF15 short hairpin RNA, together with the HBV genome into the mouse liver using hydrodynamic injection, resulted in a significant reduction in viral gene expression and DNA replication. Additionally, mutations in the KLF15 response element in the HBV core promoter significantly reduced viral DNA levels in the mouse serum. Conclusion: KLF15 is a novel transcriptional activator for HBV core and surface promoters. It is possible that KLF15 may serve as a potential therapeutic target to reduce HBV gene expression and viral replication. (HEPATOLOGY 2011;)

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