摘要
乙型肝炎病毒(HBV)慢性感染是导致肝硬化和诱发肝癌的重要因素。我国有超过一亿人的乙肝病毒携带者,50%以上的原发性肝癌来自慢性乙肝患者。世界范围内,人们对乙肝病毒的感染和其所致病理发展还缺乏有效的预防和干预手段。黏病毒抗性蛋白A(MxA)是由Ⅰ型干扰素诱导表达的人体天然免疫蛋白,主要分布在细胞质中,属于动力蛋白超家族,具有鸟苷三磷酸酶活性,能够自我组装发生寡聚化。既往研究表明,MxA具有广谱的抗RNA病毒活性,如抗流感病毒、水疱性口炎病毒、索戈托病毒和麻疹病毒等。近期的研究显示MxA对属DNA病毒的乙肝病毒的复制也有抑制作用,但具体的机制尚不明确。
本课题旨在研究MxA蛋白对乙肝病毒的抑制作用并解析其分子细胞学机制,为探索乙肝治疗的新途径提供理论依据。我们广泛运用了分子手段、生化手段、细胞共聚焦成像、活细胞实时跟踪和光漂白技术,深入研究了相关蛋白的相互作用、细胞内动力学、HBV病毒复制周期的各个环节。我们发现,在HepG2.2.15细胞模型中,MxA能够显著下调细胞外乙肝病毒表面抗原HBsAg的量、细胞内外乙肝病毒DNA的水平和核衣壳pgRNA的水平,但并不影响核心抗原HBcAg的合成和乙肝病毒mRNA的转录和核质分布,而且MxA对乙肝病毒的这些作用并不依赖其鸟苷三磷酸酶活性。进一步的研究表明,MxA通过其中心互作区CID结构域直接跟HBV的核心抗原HBcAg相互作用,二者形成蛋白复合物聚集在肝细胞核周,限制了HBcAg的细胞内运动,从而阻碍了病毒核衣壳在肝细胞内的组装。我们还鉴定出核周MxA-HBcAg蛋白聚合物的形成和维持依赖于胞内微管,而与内质网和高尔基体不存在共定位。
本研究揭示了MxA抗乙肝病毒作用的分子机制：MxA通过与乙肝病毒的核心抗原HBcAg相互作用,干扰了核衣壳的组装,进而抑制了乙肝病毒的复制。该研究结果为抗乙肝小分子药物的研发提供了新思路和理论依据。
Chronic hepatitis B virus (HBV) infection is a major risk factor for cirrhosis and hepatocellular carcinoma (HCC). In our country, more than50%of HCCs originate from the evolution of hepatitis B virus-related chronic hepatitis. Human myxovirus resistance protein A (MxA), an interferon-inducible cytoplasmic dynamin-like GTPase, possesses antiviral activity against multiple RNA viruses. Recently, MxA has also been demonstrated to have activity against the hepatitis B virus (HBV), a well-known DNA virus responsible for acute and chronic liver disease in humans. Here, we investigated the molecular mechanism for the anti-HBV activity of MxA. Our results demonstrated that in HepG2.2.15cells, MxA GTPase-independently suppressed the production of hepatitis B surface antigen (HBsAg) and HBV DNA without changing the level of hepatitis B core antigen (HBcAg) and the distribution of HBV mRNA. MxA significantly reduced the level of the encapsidated pregenomic RNA (pgRNA). Through its central interactive domain, MxA interacted with HBcAg causing accumulation of the proteins in perinuclear compartments. MxA-HBcAg interaction significantly affected the dynamics of HBcAg by immobilizing HBcAg in the perinuclear structures. Conclusion:MxA displays antiviral activity against HBV involving a mechanism of MxA-HBcAg interaction which may interfere with core particle formation. The findings provide a theoretical basis for the design of small molecules against HBV
引文
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