Type-I-IFN-Stimulated Gene TRIM5γ Inhibits HBV Replication by Promoting HBx Degradation
Guangyun Tan,
Zhaohong Yi,
Hongxiao Song,
Fengchao Xu,
Feng Li,
Roghiyh Aliyari,
Hong Zhang,
Peishuang Du,
Yanhua Ding,
Junqi Niu,
Xiaosong Wang,
Lishan Su,
F. Xiao-Feng Qin,
Genhong Cheng
Affiliations
Guangyun Tan
Department of Immunology, Institute of Translational Medicine, The First Hospital of Jilin University, Changchun, Jilin 130061, China; Corresponding author
Zhaohong Yi
CAS Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Chaoyang District, Beijing, China
Hongxiao Song
Department of Immunology, Institute of Translational Medicine, The First Hospital of Jilin University, Changchun, Jilin 130061, China
Fengchao Xu
Department of Immunology, Institute of Translational Medicine, The First Hospital of Jilin University, Changchun, Jilin 130061, China
Feng Li
Lineberger Comprehensive Cancer Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
Roghiyh Aliyari
Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, CA 90095, USA
Hong Zhang
Phase I Clinical Research Center, The First Hospital of Jilin University, Jilin 130021, China
Peishuang Du
CAS Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Chaoyang District, Beijing, China
Yanhua Ding
Phase I Clinical Research Center, The First Hospital of Jilin University, Jilin 130021, China
Junqi Niu
Department of Hepatology, The First Hospital of Jilin University, Changchun, Jilin 130021, China
Xiaosong Wang
Department of Immunology, Institute of Translational Medicine, The First Hospital of Jilin University, Changchun, Jilin 130061, China
Lishan Su
Department of Immunology, Institute of Translational Medicine, The First Hospital of Jilin University, Changchun, Jilin 130061, China; CAS Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Chaoyang District, Beijing, China; Lineberger Comprehensive Cancer Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
F. Xiao-Feng Qin
Center of Systems Medicine, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100005, China; Suzhou Institute of Systems Medicine, Suzhou, Jiangsu 215123, China; Corresponding author
Genhong Cheng
Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, CA 90095, USA; Corresponding author
Summary: To understand the molecular mechanisms that mediate the anti-hepatitis B virus (HBV) effect of interferon (IFN) therapy, we conduct high-throughput bimolecular fluorescence complementation screening to identify potential physical interactions between the HBx protein and 145 IFN-stimulated genes (ISGs). Seven HBx-interacting ISGs have consistent and significant inhibitory effects on HBV replication, among which TRIM5γ suppresses HBV replication by promoting K48-linked ubiquitination and degradation of the HBx protein on the K95 ubiquitin site. The B-Box domain of TRIM5γ under overexpression conditions is sufficient to trigger HBx degradation and is responsible both for interacting with HBx and recruiting TRIM31, which is an ubiquitin ligase that triggers HBx ubiquitination. High expression levels of TRIM5γ in IFN-α-treated HBV patients might indicate a better therapeutic effect. Thus, our studies identify a crucial role for TRIM5γ and TRIM31 in promoting HBx degradation, which may facilitate the development of therapeutic agents for the treatment of patients with IFN-resistant HBV infection. : In brief, Tan et al. find that IFN-induced TRIM5γ recruits TRIM31 to degrade HBx, resulting in suppression of hepatitis B virus replication. Keywords: type I IFN, HBV, HBx, TRIM5γ, TRIM31
