乙型肝炎病毒基因表达和复制由肝细胞核因子6抑制

StephenW

Inhibition of Hepatitis B Virus Gene Expression and Replication by Hepatocyte Nuclear Factor 6

    Ruidong Hao a,
    Jing He a,
    Xing Liu a,
    Guozhen Gao c,
    Dan Liu b,
    Lei Cui a,
    Guojun Yu a,
    Wenhui Yu a,
    Yu Chen a and
    Deyin Guo a,b

    aState Key Laboratory of Virology and Modern Virology Research Center, College of Life Sciences, Wuhan University, Wuhan, Hubei, China
    bSchool of Basic Medical Sciences, Wuhan University, Wuhan, Hubei, China
    cDepartment of Molecular Carcinogenesis, the University of Texas MD Anderson Cancer Center, Smithville, Texas, USA

    J.-H. J. Ou, Editor

- Author Affiliations
ABSTRACT

Hepatitis B virus (HBV), a small enveloped DNA virus, chronically infects more than 350 million people worldwide and causes liver diseases from hepatitis to cirrhosis and liver cancer. Here, we report that hepatocyte nuclear factor 6 (HNF6), a liver-enriched transcription factor, can inhibit HBV gene expression and DNA replication. Overexpression of HNF6 inhibited, while knockdown of HNF6 expression enhanced, HBV gene expression and replication in hepatoma cells. Mechanistically, the SP2 promoter was inhibited by HNF6, which partly accounts for the inhibition on S mRNA. Detailed analysis showed that a cis element on the HBV genome (nucleotides [nt] 3009 to 3019) was responsible for the inhibition of the SP2 promoter by HNF6. Moreover, further analysis showed that HNF6 reduced viral pregenomic RNA (pgRNA) posttranscriptionally via accelerating the degradation of HBV pgRNA independent of La protein. Furthermore, by using truncated mutation experiments, we demonstrated that the N-terminal region of HNF6 was responsible for its inhibitory effects. Importantly, introduction of an HNF6 expression construct with the HBV genome into the mouse liver using hydrodynamic injection resulted in a significant reduction in viral gene expression and DNA replication. Overall, our data demonstrated that HNF6 is a novel host factor that can restrict HBV replication via both transcriptional and posttranscriptional mechanisms.

IMPORTANCE HBV is a major human pathogen whose replication is regulated by host factors. Liver-enriched transcription factors are critical for many liver functions, including metabolism, development, and cell proliferation, and some of them have been shown to regulate HBV gene expression or replication in different manners. In this study, we showed that HNF6 could inhibit the gene expression and DNA replication of HBV via both transcriptional and posttranscriptional mechanisms. As HNF6 is differentially expressed in men and women, the current results may suggest a role of HNF6 in the gender dimorphism of HBV infection.
FOOTNOTES

        Received 23 October 2014.
        Accepted 26 January 2015.
        Accepted manuscript posted online 4 February 2015.
    Address correspondence to Deyin Guo, [email protected].

    Citation Hao R, He J, Liu X, Gao G, Liu D, Cui L, Yu G, Yu W, Chen Y, Guo D. 2015. Inhibition of hepatitis B virus gene expression and replication by hepatocyte nuclear factor 6. J Virol 89:4345–4355. doi:10.1128/JVI.03094-14.

StephenW

乙型肝炎病毒基因表达和复制由肝细胞核因子6抑制

    瑞东浩一，
    荆荷一，
    邢柳一，
    果珍高C，
    刘丹B，
    雷衰一，
    国军羽，
    文汇羽，
    于砗嗯一和
    德音过A，B

    病毒学及现代病毒学研究中心，生命科学学院，武汉大学，武汉，湖北，中国的国家重点实验室
    基础医学研究所，武汉大学，武汉，湖北，中国的B校
    分子致癌，得克萨斯大学MD安德森癌症中心的大学，史密斯维尔，美国德克萨斯州了C系

    J.-H. J.欧，编辑器

- 作者所属机构
摘要

乙型肝炎病毒（HBV），小包膜DNA病毒，感染慢性全世界有超过3.5亿人，并导致肝病肝炎到肝硬化和肝癌。在这里，我们报告说，肝细胞核因子6（HNF6），肝富集转录因子，能抑制HBV基因表达和DNA的复制。 HNF6的过表达抑制，而HNF6表达的敲低提高，乙型肝炎病毒的基因表达和复制在肝癌细胞。机械，SP2的启动子被抑制HNF6，这部分占在S基因的抑制。详细的分析表明，在HBV基因组中的CIS元件（核苷酸[NT] 3009至3019）负责对SP2子由HNF6的抑制作用。此外，进一步的分析表明，HNF6通过加快香格里拉蛋白质的HBV pgRNA独立降解减少病毒前基因组RNA（pgRNA）转录后水平。此外，通过使用截短突变实验，我们表明，HNF6的N末端区域，负责其抑制作用。重要的是，引入HNF6表达的构建与HBV基因组成使用高压注射导致显著减少病毒基因表达和DNA复制的小鼠肝。总的来说，我们的数据表明，HNF6是能够通过转录和转录后机制限制HBV复制一个新的宿主因子。

重要性HBV是主要的人类病原体的复制是通过宿主因素调节。肝富集转录因子是许多肝脏功能，包括代谢，发育，细胞增殖至关重要的，其中一些已显示出调节以不同的方式的HBV基因表达或复制。在这项研究中，我们发现，HNF6可以通过转录和转录后机制抑制HBV的基因表达和DNA的复制。由于HNF6的差异表达的男性和女性，目前的结果可能表明HNF6在HBV感染的性别二态性的作用。
脚注

        收到的2014年10月23日。
        接受2015年1月26日。
        接受手稿在网上发布4月到2015年。
    地址对应于德音郭[email protected]。

    引文浩R，他Ĵ，刘X，高G，刘D，崔L，俞G，渝W，陈Y，郭D. 2015年抑制乙肝病毒基因的表达和复制由肝细胞核因子6病毒学杂志89：4345-4355。 DOI：10.1128 / JVI.03094-14。

战天斗hbv

我个人觉得、这个、恐怕也就是发发论文了、看不到药物的