Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, Shanghai Institute of Infectious Diseases and Biosecurity,National Medical Center for Infectious Diseases, Huashan Hospital, Fudan University, Shanghai 200040, China.
Key Laboratory of Medical Molecular Virology (Ministry of Education/National Health Commission/Chinese Academy of Medical Sciences), Department of Microbiology and Parasitology, Shanghai Institute of Infectious Diseases and Biosecurity, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai 200032, China.
Nucleic Acids Res. 2022 Feb 28;50(4):2157-2171. doi: 10.1093/nar/gkac070.
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.
慢性乙型肝炎病毒 (HBV) 感染与肝硬化和肝细胞癌有关。HBV 共价闭合环状 DNA (cccDNA) 感染肝细胞后，作为组蛋白结合的迷你染色体存在，受到类似于染色体 DNA 的转录调控。在这里，我们确定高迁移率族蛋白 AT 钩 1 (HMGA1) 蛋白是 HBV 转录的正调节剂，它与增强子 II/核心启动子 (EII/Cp) 内的保守 ATTGG 位点结合，并招募转录因子 FOXO3α 和 PGC1α。HMGA1 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，HBV 还证明了内源性 HMGA1 的表达上调，这涉及 HBV X 蛋白 (HBx) 与 SP1 转录因子相互作用以激活 HMGA1 启动子。与这些体外结果一致，免疫耐受期的慢性乙型肝炎患者的肝内 HMGA1 蛋白水平和血清 HBV 标志物均高于非活动携带者期的患者。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 HMGA1 有助于 HBV 清除。这些数据确立了 HMGA1 作为 HBV 的重要正调节剂，HBV 通过 HBx 对其进行反向上调，并提示 HMGA1-HBV 正反馈回路可能是一个潜在的治疗靶点。
