摘要
Background: Ubiquitination plays an essential role in many biological processes, including viral infection, and can be reversed by deubiquitinating enzymes (DUBs). Although some studies discovered that DUBs inhibit or enhance viral infection by various mechanisms, there is lack of information on the role of DUBs in virus regulation, which needs to be further investigated.Methods: Immunoblotting, real-time polymerase chain reaction,in vivo/in vitro deubiquitination, protein immunoprecipitation, immunofluorescence, and co-localization biological techniques were employed to examine the effect of ubiquitin-specific protease 3 (USP3) on APOBEC3G (A3G) stability and human immunodeficiency virus (HIV) replication. To analyse the relationship between USP3 and HIV disease progression, we recruited 20 HIV-infected patients to detect the levels of USP3 and A3G in peripheral blood and analysed their correlation with CD4^(+) T-cell counts. Correlation was estimated by Pearson correlation coefficients (for parametric data).Results: The results demonstrated that USP3 specifically inhibits HIV-1 replication in an A3G-dependent manner. Further investigation found that USP3 stabilized 90% to 95% of A3G expression by deubiquitinating Vif-mediated polyubiquitination and blocking its degradation in an enzyme-dependent manner. It also enhances the A3G messenger RNA (mRNA) level by binding to A3G mRNA and stabilizing it in an enzyme-independent manner. Moreover, USP3 expression was positively correlated with A3G expression (r= 0.5110) and CD4^(+) T-cell counts (r= 0.5083) in HIV-1-infected patients.Conclusions: USP3 restricts HIV-1 viral infections by increasing the expression of the antiviral factor A3G. Therefore, USP3 may be an important target for drug development and serve as a novel therapeutic strategy against viral infections.
基金
This work was supported in part by,grants from the National Key R&D Program of China(Nos.2021YFC2301900 and 2301904)
the National Natural Science Foundation of China(Nos.81930062,81672004 to ZWY,and 31900457,82272304 to GWY)
the Science and Technology Department,of Jilin_Province,(Nos.20190101003JH,20200201422JC,20190201272JC,YDZJ202201ZYTS671,and YDZJ202201ZYTS590)
Program of Jilin Finance Department(No.2019SRCJ017)
the Key Laboratory of Molecular Virology,Jilin Province(No.20102209).
作者简介
Simin Zhao,contributed equally to this work;Baisong Zheng,contributed equally to this work;Correspondence to:Prof.Wenyan Zhang,Center for Pathogen Biology and Infectious Diseases,Institute of Virology and AIDS Research,the First Hospital of Jilin University.No 519 East Minzhu Avenue,Changchun 130021,China E-Mail:zhangwenyan@jlu.edu.cn;Correspondence to:Prof.Wenying Gao,Center for Pathogen Biology and Infectious Diseases,Institute of Virology and AIDS Research,The First Hospital of Jilin University.No 519 East Minzhu Avenue,Changchun 130021,China E-Mail:gaowenying@jlu.edu.cn;Correspondence to:Prof.Zhuo Li,Department of Endocrinology and Metabolism,The First Hospital of Jilin University.No 1 Xinmin Avenue,Changchun,Jilin 130021,China E-Mail:zhuoli@jlu.edu.cn。
