Li Yujia, Li Shilin, Duan Xiaoqiong, Chen Yanzhao, Jiao Baihai, Ye Haiyan, Yao Min, Chen Limin
Institute of Blood Transfusion, Chinese Academy of Medical Sciences and Peking Union Medical College, Key Laboratory for Transfusion-Transmitted Diseases of Sichuan Province, Chengdu, Sichuan 610052, China.
Institute of Blood Transfusion, Chinese Academy of Medical Sciences and Peking Union Medical College, Key Laboratory for Transfusion-Transmitted Diseases of Sichuan Province, Chengdu, Sichuan 610052, China; Toronto General Research Institute, University of Toronto, Toronto, ON, Canada M5G 1L6.
Mediators Inflamm. 2016;2016:7417648. doi: 10.1155/2016/7417648. Epub 2016 Oct 27.
Hepatitis B virus (HBV) is an important account of infectious hepatitis and interferon (IFN) remains one of the best treatment options. Activation of type I IFN signaling pathway leads to expressions of IFN-stimulated genes (ISGs) which play important roles in antiviral and immunomodulatory responses to HBV or hepatitis C virus (HCV) infection. Our previous studies indicated that ISG15 and its conjugation (ISGylation) were exploited by HCV to benefit its replication and persistent infection. This study was designed to assess the role of ISG15 and ISGylation in HBV infection . The levels of ISG15 and ISGylation were upregulated by ISG15 plasmid transfection into HepG2.2.15 cells. Decreased ISGylation was achieved by siRNA targeting UBE1L, the only E1 activating enzyme for ISGylation. Overexpression of ISG15 and subsequent ISGylation significantly increased the levels of HBV DNA in the culture supernatants although the intracellular viral replication remained unaffected. Silencing UBE1L, with decreased ISGylation achieved, abrogated this ISGylation-mediated promoting effect. Our data indicated that overexpression of ISG15 stimulated HBV production in an ISGylation-dependent manner. Identification of ISG15-conjugated proteins (either HBV viral or host proteins) may reveal promising candidates for further antiviral drug development.
乙型肝炎病毒（HBV）是传染性肝炎的重要病因，干扰素（IFN）仍然是最佳治疗选择之一。I型干扰素信号通路的激活会导致干扰素刺激基因（ISGs）的表达，这些基因在对HBV或丙型肝炎病毒（HCV）感染的抗病毒和免疫调节反应中发挥重要作用。我们之前的研究表明，HCV利用ISG15及其缀合作用（ISGylation）来促进其复制和持续感染。本研究旨在评估ISG15和ISGylation在HBV感染中的作用。通过将ISG15质粒转染到HepG2.2.15细胞中，上调了ISG15和ISGylation的水平。通过靶向ISGylation唯一的E1激活酶UBE1L的小干扰RNA（siRNA）降低了ISGylation水平。尽管细胞内病毒复制未受影响，但ISG15的过表达及随后的ISGylation显著增加了培养上清液中HBV DNA的水平。沉默UBE1L并降低ISGylation水平，消除了这种ISGylation介导的促进作用。我们的数据表明，ISG15的过表达以ISGylation依赖的方式刺激HBV产生。鉴定ISG15缀合蛋白（无论是HBV病毒蛋白还是宿主蛋白）可能会为进一步开发抗病毒药物揭示有前景的候选物。
