Kim Jung-Hwan, Luo Jiann-Kae, Zhang Dong-Er
Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA.
J Immunol. 2008 Nov 1;181(9):6467-72. doi: 10.4049/jimmunol.181.9.6467.
Hepatitis B virus (HBV) causes both acute and chronic infection of the human liver and is associated with the development of liver cirrhosis and hepatocellular carcinoma. UBP43 (USP18) is known as an ISG15-deconjugating enzyme and an inhibitor of type I IFN signaling independent of its enzyme activity. In this study, we examined the role of these two previously identified functions of UBP43 in the innate immune response to HBV viral infection. As an in vivo HBV replication model system, a replication-competent DNA construct was injected hydrodynamically into the tail veins of mice. Although the lack of ISG15 conjugation in the absence of ISG15-activating enzyme UBE1L (UBA7) did not affect the level of HBV replication, the steady-state level of HBV DNA was substantially reduced in the UBP43-deficient mice in comparison to the wild-type controls. In addition, introduction of short hairpin RNA against UBP43 resulted in substantially lower levels of HBV DNA at day 4 postinjection and higher levels of ISG mRNAs. These results suggest that HBV infection is more rapidly cleared if UBP43 expression is reduced. Furthermore, these results illustrate the therapeutic potential of modulating UBP43 levels in treating viral infection, especially for viruses sensitive to IFN signaling.
乙型肝炎病毒（HBV）可引起人类肝脏的急性和慢性感染，并与肝硬化和肝细胞癌的发生有关。UBP43（USP18）是一种已知的ISG15去缀合酶，也是一种不依赖其酶活性的I型干扰素信号传导抑制剂。在本研究中，我们研究了UBP43这两种先前确定的功能在对HBV病毒感染的先天免疫反应中的作用。作为一种体内HBV复制模型系统，将一种具有复制能力的DNA构建体通过尾静脉水动力注射到小鼠体内。虽然在缺乏ISG15激活酶UBE1L（UBA7）的情况下缺乏ISG15缀合并不影响HBV复制水平，但与野生型对照相比，UBP43缺陷小鼠中HBV DNA的稳态水平显著降低。此外，引入针对UBP43的短发夹RNA导致注射后第4天HBV DNA水平显著降低，ISG mRNA水平升高。这些结果表明，如果UBP43表达降低，HBV感染能被更快清除。此外，这些结果说明了调节UBP43水平在治疗病毒感染，特别是对干扰素信号敏感的病毒方面的治疗潜力。
