HMGB1 Promotes Hepatitis C Virus Replication by Interaction with Stem-Loop 4 in the Viral 5′ Untranslated Region
HMGB1 Promotes Hepatitis C Virus Replication by Interaction with Stem-Loop 4 in the Viral 5′ Untranslated Region
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DOI：
10.1128/jvi.02795-15
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发表时间：
2015-12
影响因子：
5.4
通讯作者：
Rong Yu;Darong Yang;Shaohua Lei;Xiaohong Wang;Xianghe Meng;Binbin Xue;Haizhen Zhu
中科院分区：
文献类型：
--
作者：
Rong Yu;Darong Yang;Shaohua Lei;Xiaohong Wang;Xianghe Meng;Binbin Xue;Haizhen Zhu
高迁移率族蛋白1（HMGB1）是一种高度保守的核蛋白，与多种人类疾病有关，包括感染性疾病、免疫性疾病、代谢性疾病和癌症。HMGB1由两个串联的HMG盒（A盒和B盒）组成，所述盒含有DNA结合结构域和酸性C末端肽。据报道，HMGB1通过与病毒蛋白结合来增强病毒复制。然而，其在丙型肝炎病毒（HCV）复制中的作用尚不清楚。在这里，我们表明，HMGB1促进HCV复制，但对HCV翻译没有影响。RNA免疫沉淀实验表明，HCV RNA的正链，而不是负链与HMGB1相互作用。HCV感染后，HMGB1蛋白从细胞核转位到细胞质，并与HCV基因组相互作用。此外，HMGB1的A box是与HCV 5′非翻译区的茎环4（SL4）相互作用的关键结构域。HMGB1 A盒的缺失消除了HMGB1对HCV复制的增强作用。我们的数据表明，HMGB1作为HCV的前病毒因子，通过与HCV基因组相互作用促进病毒在肝细胞中的复制。重要性丙型肝炎病毒（HCV）是全球主要的健康威胁，影响全球超过1.7亿人感染。这些患者发生严重肝病的风险很高，如慢性肝炎、肝硬化和肝细胞癌。目前还没有疫苗。许多宿主因素可能与HCV相关疾病的发病机制有关。在这项研究中，我们发现了一个新的HCV RNA结合蛋白，HMGB1，促进HCV RNA复制。HCV基因组5′端非翻译区的SL4是HMGB1结合的关键区域，HMGB1蛋白的A box是与HCV RNA相互作用、促进病毒复制的功能域。HMGB1在HCV相关疾病中起重要作用，HMGB1在HCV发病机制中的具体作用有待进一步研究。
ABSTRACT High-mobility group box 1 (HMGB1) protein is a highly conserved nuclear protein involved in multiple human diseases, including infectious diseases, immune disorders, metabolic disorders, and cancer. HMGB1 is comprised of two tandem HMG boxes (the A box and the B box) containing DNA-binding domains and an acidic C-terminal peptide. It has been reported that HMGB1 enhances viral replication by binding to viral proteins. However, its role in hepatitis C virus (HCV) replication is unknown. Here, we show that HMGB1 promoted HCV replication but had no effect on HCV translation. RNA immunoprecipitation experiments indicated that the positive strand, not the negative strand, of HCV RNA interacted with HMGB1. HCV infection triggered HMGB1 protein translocation from the nucleus to the cytoplasm, in which it interacted with the HCV genome. Moreover, the A box of HMGB1 is the pivotal domain to interact with stem-loop 4 (SL4) of the HCV 5′ untranslated region. Deletion of the HMGB1 A box abrogated the enhancement of HCV replication by HMGB1. Our data suggested that HMGB1 serves as a proviral factor of HCV to facilitate viral replication in hepatocytes by interaction with the HCV genome. IMPORTANCE Hepatitis C virus (HCV) is a major global health threat, affecting more than 170 million people infection worldwide. These patients are at high risk of developing severe liver diseases such as chronic hepatitis, cirrhosis, and hepatocellular carcinoma. Currently, no vaccine is available. Many host factors may be implicated in the pathogenesis of HCV-related diseases. In this study, we found a novel HCV RNA-binding protein, HMGB1, that promotes HCV RNA replication. Moreover, SL4 in the 5′ untranslated region of the HCV genome is the key region for HMGB1 binding, and the A box of HMGB1 protein is the functional domain to interact with HCV RNA and enhance viral replication. HMGB1 appears to play an important role in HCV-related diseases, and further investigation is warranted to elucidate the specific actions of HMGB1 in HCV pathogenesis.