title: Ubiquitin ligase Fbw7 restricts the replication of hepatitis C virus by targeting NS5B for ubiquitination and degradation.
abstract: The nonstructural protein 5B (NS5B) of hepatitis C virus (HCV) is an RNA-dependent RNA polymerase (RdRp) and responsible for replicating the whole HCV genome with help of viral and cellular proteins. However, how cellular factors influence NS5B and, in turn, regulating HCV replication are still poorly defined. The well known tumor suppressor Fbw7, a component of E3 ubiquitin ligase SCF(Fbw7), targets oncoproteins or cellular regulatory proteins for ubiquitin-mediated degradation through a highly conserved binding site called a Cdc4 phosphodegron (CPD). But little is known about whether Fbw7 plays a role in regulation of viral proteins. In this study, we revealed that the conserved CPD is shared by NS5B of almost all genotype of HCV and our data demonstrated that NS5B is a bona fide substrate of Fbw7. Forced expression of Fbw7 promoted the ubiquination of NS5B and negatively regulated its turnover in the proteasome-dependent manner. We further revealed the interaction between NS5B and Fbw7, which resulted in the relocation of Fbw7 from nucleus to cytoplasm. During HCV replication, ectopic expression of Fbw7 could strongly down-regulate NS5B level and consequently inhibited the virus replication. When endogenous Fbw7 was knocked down, both NS5B protein abundance and HCV replication were remarkably up-regulated. The results provide more insights into the interplay of HCV and cellular factors and shed light on molecular mechanisms of HCV replication and pathogenesis.
authors.affiliation: State Key Laboratory of Virology and Modern Virology Research Center, College of Life Sciences, Wuhan University, Wuhan, Hubei 430072, PR China.
authors.forename: Jun
authors.initials: J
authors.lastname: Chen
authors.affiliation: Bio-Thera Solutions, Ltd. Co., Enterprise Accelerator A6-5fl, 11 Kaiyuan Rd, Science City, Guangzhou 510530, PR China.
authors.forename: Xiaoyun
authors.initials: X
authors.lastname: Wu
authors.affiliation: State Key Laboratory of Virology and Modern Virology Research Center, College of Life Sciences, Wuhan University, Wuhan, Hubei 430072, PR China.
authors.forename: Shiyou
authors.initials: S
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Virology and Modern Virology Research Center, College of Life Sciences, Wuhan University, Wuhan, Hubei 430072, PR China.
authors.forename: Shuliang
authors.initials: S
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Virology and Modern Virology Research Center, College of Life Sciences, Wuhan University, Wuhan, Hubei 430072, PR China.
authors.forename: Nian
authors.initials: N
authors.lastname: Xiang
authors.affiliation: State Key Laboratory of Virology and Modern Virology Research Center, College of Life Sciences, Wuhan University, Wuhan, Hubei 430072, PR China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Virology and Modern Virology Research Center, College of Life Sciences, Wuhan University, Wuhan, Hubei 430072, PR China; School of Basic Medical Sciences, Wuhan University, Wuhan, Hubei 430072, PR China. Electronic address: dguo@whu.edu.cn.
authors.forename: Deyin
authors.initials: D
authors.lastname: Guo
mesh_terms: D018797:Cell Cycle Proteins / Q000378:metabolism*; D002460:Cell Line; D044783:F-Box Proteins / Q000378:metabolism*; D000073979:F-Box-WD Repeat-Containing Protein 7; D016174:Hepacivirus / Q000502:physiology*; D022781:Hepatocytes / Q000378:metabolism / Q000821:virology*; D006801:Humans; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D054875:Ubiquitination / Q000502:physiology*; D017361:Viral Nonstructural Proteins / Q000378:metabolism*; D014779:Virus Replication / Q000502:physiology*; D012324:RNA-Dependent RNA Polymerase
chemical_list: D018797:Cell Cycle Proteins; D044783:F-Box Proteins; D000073979:F-Box-WD Repeat-Containing Protein 7; D044767:Ubiquitin-Protein Ligases; D017361:Viral Nonstructural Proteins; C513273:FBXW7 protein, human; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase
keywords: Degradation; Fbw7; HCV replication; NS5B; Ubiquitination