Sirtuin 1 Regulates Hepatitis B Virus Transcription and Replication by Targeting Transcription Factor AP-1
Sirtuin 1 Regulates Hepatitis B Virus Transcription and Replication by Targeting Transcription Factor AP-1
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Sirtuin 1 通过靶向转录因子 AP-1 调节乙型肝炎病毒转录和复制
DOI：
10.1128/jvi.02861-13
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发表时间：
2014-03-01
影响因子：
5.4
通讯作者：
Chen, Juan
中科院分区：
文献类型：
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作者：
Ren, Ji-Hua;Tao, Ying;Chen, Juan
慢性B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，HBV复制的分子机制仍然是难以捉摸的。SIRT 1是一种III类组蛋白脱乙酰酶，是HBV cccDNA微型染色体的结构组分。在这项研究中，我们发现通过使用基于微阵列的基因表达谱分析，SIRT 1在HBV表达细胞中上调。SIRT 1基因沉默显著抑制HBV DNA复制中间体、3.5 kb mRNA和核心蛋白水平。相反，SIRT 1的过表达增强了HBV的复制。SIRT 1通过靶向转录因子AP-1增强HBV核心启动子的活性。通过染色质免疫沉淀试验证明，AP-1的c-Jun亚基与HBV核心启动子区结合。AP-1结合位点的突变或AP-1的敲低可消除SIRT 1对HBV复制的影响。最后，SIRT 1抑制剂sirtinol也抑制了HBV DNA复制中间体，以及3.5-kb mRNA。我们的研究发现了一种新型宿主因子SIRT 1，它可能促进HBV在肝细胞中的复制。这些数据表明了使用SIRT 1抑制剂治疗HBV感染的基本原理。
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.