The Level of Hepatitis B Virus Replication Is Not Affected by Protein ISG15 Modification but Is Reduced by Inhibition of UBP43 (USP18) Expression
The Level of Hepatitis B Virus Replication Is Not Affected by Protein ISG15 Modification but Is Reduced by Inhibition of UBP43 (USP18) Expression
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DOI：
10.4049/jimmunol.181.9.6467
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发表时间：
2008-11-01
影响因子：
4.4
通讯作者：
Zhang, Dong-Er
中科院分区：
文献类型：
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作者：
Kim, Jung-Hwan;Luo, Jiann-Kae;Zhang, Dong-Er
乙肝病毒可引起人类肝脏的急性和慢性感染，并与肝硬变和肝细胞癌的发生有关。UBP43(USP18)是一种ISG15去结合酶，是I型干扰素信号的抑制因子，不依赖于其酶活性。在这项研究中，我们研究了UBP43的这两个先前已确定的功能在对乙肝病毒感染的先天免疫反应中的作用。作为体内乙肝病毒复制模型系统，将复制能力强的DNA构建体液动力注射到小鼠尾静脉中。虽然在没有ISG15激活酶UBE1L(UBA7)的情况下没有ISG15偶联，但与野生型对照相比，UBP43缺陷小鼠的HBVDNA稳态水平显著降低。此外，针对UBP43的短发夹RNA的引入导致注射后第4天的HBVDNA水平显著降低，而ISG mRNAs水平更高。这些结果表明，如果UBP43的表达减少，乙肝病毒感染就会更快地被清除。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的治疗潜力。免疫学杂志，2008,181：6467-6472。
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. The Journal of Immunology, 2008, 181: 6467-6472.