Prospero-related homeobox protein (Prox1) inhibits hepatitis B virus replication through repressing multiple cis regulatory elements
Prospero-related homeobox protein (Prox1) inhibits hepatitis B virus replication through repressing multiple cis regulatory elements
复制标题
Prospero相关同源盒蛋白（Prox1）通过抑制多个顺式调控元件抑制乙型肝炎病毒复制
DOI：
10.1099/vir.0.006007-0
复制
发表时间：
2009-05-01
影响因子：
3.8
通讯作者：
Xie, Youhua
中科院分区：
文献类型：
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作者：
Qin, Jun;Zhai, Jianwei;Xie, Youhua
B型肝炎病毒（HBV）基因转录受病毒启动子和增强子控制，其活性受许多细胞因子以及病毒编码蛋白的调节。细胞因子对HBV顺式元件活性的负调节报道不如其激活广泛。在这项研究中，我们报告，核因子Prox pero相关的同源异型盒蛋白（Prox 1）抑制HBV抗原表达和基因组复制在培养的肝细胞。通过使用转录因子基因分析，四个HBV启动子中的三个，即增强子II/核心启动子（ENII/Cp），preS 1启动子（Sp1）和增强子I/X启动子，被鉴定为Prox 1介导的抑制的靶点。机制分析表明，对于ENII/Cp，Prox 1作为肝受体同源物1（LRH-1）的辅阻遏物，下调LRH-1介导的ENII/Cp激活，而对于Sp1，Prox 1通过直接与肝细胞核因子1相互作用部分抑制Spl活性。鉴定Prox 1作为HBV阻遏物将有助于了解病毒顺式元件和宿主细胞因子之间的详细相互作用，也可能形成新的抗HBV干预疗法的基础。
Hepatitis B virus (HBV) gene transcription is controlled by viral promoters and enhancers, the activities of which are regulated by a number of cellular factors as well as virally encoded proteins. Negative regulation of HBV cis-element activities by cellular factors has been reported less widely than their activation. In this study, we report that nuclear factor Pros pero-related homeobox protein (Prox1) represses HBV antigen expression and genome replication in cultured hepatocytes. By using reporter-gene analysis, three of the four HBV promoters, namely the enhancer II/core promoter (ENII/Cp), preS1 promoter (Sp1) and enhancer I/X promoter, were identified as targets for Prox1-mediated repression. Mechanistic analysis then revealed that, for ENII/Cp, Prox1 serves as a corepressor of liver receptor homologue 1 (LRH-1) and downregulates LRH-1-mediated activation of ENII/Cp, whereas for Sp1, Prox1 partially represses Spl activity by interacting directly with hepatocyte nuclear factor 1. Identification of Prox1 as an HBV repressor will help in the understanding of detailed interactions between viral cis elements and host cellular factors and may also form the basis for new anti-HBV intervention therapeutics.