Deubiquitinase ubiquitin-specific protease 3 (USP3) inhibits HIV-1 replication via promoting APOBEC3G (A3G) expression in both enzyme activity-dependent and -independent manners  

作　　者：Simin Zhao Baisong Zheng Liuli Wang Wenzhe Cui Chunlai Jiang Zhuo Li Wenying Gao Wenyan Zhang 

机构地区：[1]Center for Pathogen Biology and Infectious Diseases,Institute of Virology and AIDS Research,Key Laboratory of Organ Regeneration and Transplantation of The Ministry of Education,The First Hospital of Jilin University,Changchun,Jilin 130021,China [2]College of Life Science of Jilin University,Changchun,Jilin 130012,China [3]Department of Regenerative Medicine,School of Pharmaceutical Sciences,Jilin University,Changchun,Jilin 130012,China [4]Jilin Provincial Key Laboratory on Molecular and Chemical Genetics,The Second Hospital of Jilin University,Changchun,Jilin 130041,China [5]Department of Endocrinology and Metabolism,The First Hospital of Jilin University,Changchun,Jilin 130021,China

出　　处：《Chinese Medical Journal》2022年第22期2706-2717,共12页中华医学杂志（英文版）

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).

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.

关 键 词：APOBEC3G Ubiquitin-specific protease 3 DEUBIQUITINATION Human immunodeficiency virus-1 Vif Human immunodeficiency virus Deubiquitinase 

分 类 号：R512.91[医药卫生—内科学]