The Hepatitis B Virus X Protein Disrupts Innate Immunity by Downregulating Mitochondrial Antiviral Signaling Protein
The Hepatitis B Virus X Protein Disrupts Innate Immunity by Downregulating Mitochondrial Antiviral Signaling Protein
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乙型肝炎病毒 X 蛋白通过下调线粒体抗病毒信号蛋白来破坏先天免疫
DOI：
10.4049/jimmunol.0903874
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发表时间：
2010-07-15
影响因子：
4.4
通讯作者：
Zhong, Hui
中科院分区：
文献类型：
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作者：
Wei, Congwen;Ni, Caifei;Zhong, Hui
先前的研究表明，甲型肝炎病毒和丙型肝炎病毒均通过切割线粒体抗病毒信号蛋白（MAVS）来抑制天然免疫。MAVS是病毒激活的信号通路的关键组成部分，该通路激活核因子 - κB和干扰素调节因子 - 3以诱导I型干扰素的产生。对于人类乙型肝炎病毒（HBV），已表明乙肝表面抗原、乙肝e抗原或乙肝病毒粒子可抑制Toll样受体诱导的抗病毒活性，使干扰素 - β产生减少以及随后干扰素刺激基因的诱导减少。然而，乙肝病毒介导的对RIG - I - MDA5通路的抑制作用尚不清楚。在本研究中，我们发现乙肝病毒抑制了肝细胞中多聚（脱氧腺苷酸 - 脱氧胸苷酸）激活的干扰素 - β的产生。具体而言，乙肝病毒X蛋白（HBX）与MAVS相互作用，并通过MAVS蛋白中的赖氨酸（136）泛素促进MAVS的降解，从而阻止干扰素 - β的诱导。对临床样本的进一步分析显示，在乙肝病毒源性肝细胞癌中MAVS蛋白下调，这与从HBX基因敲入转基因小鼠分离的原代小鼠肝细胞在感染水疱性口炎病毒时敏感性增加相关。通过建立MAVS和HBX之间的联系，本研究表明乙肝病毒可通过HBX介导的MAVS下调来靶向RIG - I信号通路，从而减弱天然免疫系统的抗病毒反应。《免疫学杂志》，2010年，185卷：1158 - 1168页
Previous studies have shown that both hepatitis A virus and hepatitis C virus inhibit innate immunity by cleaving the mitochondrial antiviral signaling (MAVS) protein, an essential component of the virus-activated signaling pathway that activates NF-kappa B and IFN regulatory factor-3 to induce the production of type I IFN. For human hepatitis B virus (HBV), hepatitis B s-Ag, hepatitis B e-Ag, or HBV virions have been shown to suppress TLR-induced antiviral activity with reduced IFN-beta production and subsequent induction of IFN-stimulated genes. However, HBV-mediated suppression of the RIG-I-MDA5 pathway is unknown. In this study, we found that HBV suppressed poly(deoxyadenylate-thymidylate)-activated IFN-beta production in hepatocytes. Specifically, hepatitis B virus X (HBX) interacted with MAVS and promoted the degradation of MAVS through Lys(136) ubiquitin in MAVS protein, thus preventing the induction of IFN-beta. Further analysis of clinical samples revealed that MAVS protein was downregulated in hepatocellular carcinomas of HBV origin, which correlated with increased sensitivities of primary murine hepatocytes isolated from HBX knock-in transgenic mice upon vesicular stomatitis virus infections. By establishing a link between MAVS and HBX, this study suggests that HBV can target the RIG-I signaling by HBX-mediated MAVS downregulation, thereby attenuating the antiviral response of the innate immune system. The Journal of Immunology, 2010, 185: 1158-1168.