沉默信息调节因子1调控乙型肝炎病毒转录和复制通过靶向转

StephenW

Sirtuin 1 Regulates Hepatitis B Virus Transcription and Replication by Targeting Transcription Factor AP-1

    Ji-Hua Ren a,
    Ying Tao a,f,
    Zhen-Zhen Zhang b,
    Wei-Xian Chen c,
    Xue-Fei Cai a,
    Ke Chen a,
    Ben C. B. Ko d,
    Chun-Li Song a,
    Long-Kuan Ran a,
    Wan-Yu Li a,
    Ai-Long Huang a,e and
    Juan Chen a,e

    aThe Second Affiliated Hospital and the Key Laboratory of Molecular Biology of Infectious Diseases designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing, China
    bDepartment of Infectious Diseases, The Children's Hospital of Chongqing Medical University, Chongqing, China
    cDepartment of Clinical Laboratory, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
    dDepartment of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong, China
    eCollaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University, Zhejiang, China
    fDepartment of Infectious Diseases, The People's Liberation Army 161 Hospital, Wuhan, China

    G. McFadden, Editor

- Author Affiliations
ABSTRACT

Chronic hepatitis B virus (HBV) infection is a major risk factor for liver cirrhosis and hepatocellular carcinoma. Nevertheless, the molecular mechanism of HBV replication remains elusive. SIRT1 is a class III histone deacetylase that is a structure component of the HBV cccDNA minichromosome. In this study, we found by using microarray-based gene expression profiling analysis that SIRT1 was upregulated in HBV-expressing cells. Gene silencing of SIRT1 significantly inhibited HBV DNA replicative intermediates, 3.5-kb mRNA, and core protein levels. In contrast, the overexpression of SIRT1 augmented HBV replication. Furthermore, SIRT1 enhanced the activity of HBV core promoter by targeting transcription factor AP-1. The c-Jun subunit of AP-1 was bound to the HBV core promoter region, as demonstrated by using a chromatin immunoprecipitation assay. Mutation of AP-1 binding site or knockdown of AP-1 abolished the effect of SIRT1 on HBV replication. Finally, SIRT1 inhibitor sirtinol also suppressed the HBV DNA replicative intermediate, as well as 3.5-kb mRNA. Our study identified a novel host factor, SIRT1, which may facilitate HBV replication in hepatocytes. These data suggest a rationale for the use of SIRT1 inhibitor in the treatment of HBV infection.
FOOTNOTES

        Received 2 October 2013.
        Accepted 5 December 2013.
    Address correspondence to Juan Chen, [email protected], or Ailong Huang, [email protected].

StephenW

沉默信息调节因子1调控乙型肝炎病毒转录和复制通过靶向转录因子AP- 1

    纪任华一，
    瀛涛A，F ，
    珍珍张宝，
    魏贤臣C，
    学飞彩一，
    陈柯一，
    奔。B.高D，
    春丽歌一曲，
    龙宽跑了，
    万佑礼一，
    艾龙黄A，E和
    陈娟A，E

    ATHE第二附属医院和由中国教育部，重庆医科大学，重庆，中国的指定传染病分子生物学重点实验室
    bDepartment传染病，重庆医科大学，重庆，中国儿童医院
    临床实验室cDepartment ，重庆医科大学，重庆，中国第二附属医院
    应用生物dDepartment及化学科技，香港理工大学，香港，中国
    eCollaborative创新中心进行诊断和治疗感染性疾病，浙江大学，浙江，中国
    传染病fDepartment ，在解放军161医院，武汉，中国

    G.麦克法登，编辑器

- 作者所属机构
摘要

慢性乙型肝炎病毒（HBV）感染是肝硬化和肝细胞癌的主要危险因素。然而，乙肝病毒复制的分子机制仍不清楚。 SIRT1是第三类组蛋白去乙酰化酶，它是乙肝病毒cccDNA的微染色体的结构成分。在这项研究中，我们发现通过使用基于微阵列的基因表达图谱分析SIRT1上调乙肝病毒表达细胞。 SIRT1的基因沉默显著抑制HBV DNA复制中间体， 3.5 kb的mRNA表达，和核心蛋白水平。与此相反， SIRT1的表达增强HBV的复制。此外，增强型SIRT1通过靶向转录因子AP- 1的HBV核心启动子的活性。在c-Jun的亚基AP-1的结合到HBV核心启动子区域，具体表现为使用染色质免疫沉淀。的AP- 1结合位点或AP-1的突变击倒取消SIRT1对HBV复制的影响。最后， SIRT1抑制剂注入sirtinol也抑制HBV DNA复制中间体，以及3.5 -kb的mRNA的表达。我们的研究发现了一种新的宿主因子， SIRT1的，这可能有利于HBV复制的肝细胞。这些数据表明对在HBV感染的治疗中使用的SIRT1抑制剂的基本原理。
脚注

      收到2013年10月2日。
        接受2013年12月5日。
    地址对应陈娟， [email protected] ，或爱龙皇， [email protected] 。