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The Level of Hepatitis B Virus Replication Is Not Affected by Protein ISG15 Modification but Is Reduced by Inhibition of UBP43 (USP18) Expression¹

Jung-Hwan Kim^2,*, Jiann-Kae Luo^3,* and Dong-Er Zhang^4,*,

^* Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA 92037; and Department of Pathology, Division of Biology, and Moores University of California San Diego Cancer Center, University of California San Diego, La Jolla, CA 92093

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 costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grants HL91549 and GM066955.

² Current address: Department of Surgery, University of Southern California, Los Angeles, CA 90033.

³ Current address: Regeneron Pharmaceuticals, Tarrytown, NY 10591.

⁴ Address correspondence and reprint requests to Dr. Dong-Er Zhang, Mail Drop 0815, Room 5328, Moores University of California San Diego Cancer Center, University of California San Diego, 3855 Health Sciences Drive, La Jolla, CA 92093. E-mail address: d7zhang{at}ucsd.edu

⁵ Abbreviations used in this paper: HBV, hepatitis B virus; ISG, IFN-stimulated gene; sh, short hairpin; LCMV, lymphocytic choriomeningitis virus; VSV, vesicular stomatitis virus.

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