High mobility group AT-hook 1 (HMGA1) is an important positive regulator of hepatitis B virus (HBV) that is reciprocally upregulated by HBV X protein.
High mobility group AT-hook 1 (HMGA1) is an important positive regulator of hepatitis B virus (HBV) that is reciprocally upregulated by HBV X protein.
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DOI：
10.1093/nar/gkac070
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发表时间：
2022-02-28
影响因子：
14.9
通讯作者：
Zhang J
中科院分区：
文献类型：
--
作者：
Shen Z;Wu J;Gao Z;Zhang S;Chen J;He J;Guo Y;Deng Q;Xie Y;Liu J;Zhang J
B型肝炎病毒（HBV）慢性感染与肝硬化和肝细胞癌有关。感染肝细胞后，HBV共价闭合环状DNA（cccDNA）以组蛋白结合的微型染色体形式存在，受到与染色体DNA相似的转录调控。在这里，我们确定高迁移率族AT钩1（HMGA 1）蛋白作为HBV转录的正调控因子，结合增强子II/核心启动子（EII/Cp）内的保守ATTGG位点，并招募转录因子FOXO 3 α和PGC 1 α。HMGA 1介导的EII/Cp上调导致病毒基因表达和基因组复制增强。值得注意的是，内源性HMGA 1的表达也被证明是由HBV上调，这涉及HBV X蛋白（HBx）与SP1转录因子相互作用以激活HMGA 1启动子。与这些体外结果一致，与非活动性携带者阶段的患者相比，免疫耐受阶段的慢性B型肝炎患者显示出更高的肝内HMGA 1蛋白水平和更高的血清HBV标志物。最后，使用HBV持续存在的小鼠模型，我们表明通过RNA干扰靶向内源性HMGA 1促进HBV清除。这些数据确立了HMGA 1作为HBV的重要正调控因子，其通过HBx被HBV间接上调，并且还表明HMGA 1-HBV正反馈环作为潜在的治疗靶点。
Chronic infection with hepatitis B virus (HBV) is associated with liver cirrhosis and hepatocellular carcinoma. Upon infection of hepatocytes, HBV covalently closed circular DNA (cccDNA) exists as histone-bound mini-chromosome, subjected to transcriptional regulation similar to chromosomal DNA. Here we identify high mobility group AT-hook 1 (HMGA1) protein as a positive regulator of HBV transcription that binds to a conserved ATTGG site within enhancer II/core promoter (EII/Cp) and recruits transcription factors FOXO3α and PGC1α. HMGA1-mediated upregulation of EII/Cp results in enhanced viral gene expression and genome replication. Notably, expression of endogenous HMGA1 was also demonstrated to be upregulated by HBV, which involves HBV X protein (HBx) interacting with SP1 transcription factor to activate HMGA1 promoter. Consistent with these in vitro results, chronic hepatitis B patients in immune tolerant phase display both higher intrahepatic HMGA1 protein levels and higher serum HBV markers compared to patients in inactive carrier phase. Finally, using a mouse model of HBV persistence, we show that targeting endogenous HMGA1 through RNA interference facilitated HBV clearance. These data establish HMGA1 as an important positive regulator of HBV that is reciprocally upregulated by HBV via HBx and also suggest the HMGA1-HBV positive feedback loop as a potential therapeutic target.
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