title: Interferon-inducible cholesterol-25-hydroxylase inhibits hepatitis C virus replication via distinct mechanisms.
abstract: Cholesterol 25-hydroxylase (CH25H) as an interferon-stimulated gene (ISG) has recently been shown to exert broad antiviral activity through the production of 25-hydroxycholesterol (25HC), which is believed to inhibit the virus-cell membrane fusion during viral entry. However, little is known about the function of CH25H on HCV infection and replication and whether antiviral function of CH25H is exclusively mediated by 25HC. In the present study, we have found that although 25HC produced by CH25H can inhibit HCV replication, CH25H mutants lacking the hydroxylase activity still carry the antiviral activity against HCV but not other viruses such as MHV-68. Further studies have revealed that CH25H can interact with the NS5A protein of HCV and inhibit its dimer formation, which is essential for HCV replication. Thus, our work has uncovered a novel mechanism by which CH25H restricts HCV replication, suggesting that CH25H inhibits viral infection through both 25HC-dependent and independent events.
authors.affiliation: 1] CAS Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Chaoyang District, Beijing, China [2] University of Chinese Academy of Sciences, Beijing, China.
authors.forename: Yongzhi
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Key Laboratory of Gene Engineering of the Ministry of Education and State Key Laboratory for Biocontrol, School of Life Sciences, Sun Yat-Sen University, Guangzhou, 510275, China.
authors.forename: Shanshan
authors.initials: S
authors.lastname: Wang
authors.affiliation: CAS Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Chaoyang District, Beijing, China.
authors.forename: Zhaohong
authors.initials: Z
authors.lastname: Yi
authors.affiliation: 1] CAS Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Chaoyang District, Beijing, China [2] University of Chinese Academy of Sciences, Beijing, China.
authors.forename: Huabin
authors.initials: H
authors.lastname: Tian
authors.affiliation: Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, CA 90095, USA.
authors.forename: Roghiyh
authors.initials: R
authors.lastname: Aliyari
authors.affiliation: Institute of Quality Standard and Testing Technology for Agro-products, CAAS.
authors.forename: Yanhua
authors.initials: Y
authors.lastname: Li
authors.affiliation: Institute of Quality Standard and Testing Technology for Agro-products, CAAS.
authors.forename: Gang
authors.initials: G
authors.lastname: Chen
authors.affiliation: CAS Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Chaoyang District, Beijing, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Liu
authors.affiliation: Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Jin
authors.initials: J
authors.lastname: Zhong
authors.affiliation: State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China.
authors.forename: Xinwen
authors.initials: X
authors.lastname: Chen
authors.affiliation: CAS Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Chaoyang District, Beijing, China.
authors.forename: Peishuang
authors.initials: P
authors.lastname: Du
authors.affiliation: 1] CAS Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Chaoyang District, Beijing, China [2] Department of Microbiology and Immunology and Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC27599, USA.
authors.forename: Lishan
authors.initials: L
authors.lastname: Su
authors.affiliation: 1] Key Laboratory of Gene Engineering of the Ministry of Education and State Key Laboratory for Biocontrol, School of Life Sciences, Sun Yat-Sen University, Guangzhou, 510275, China [2] Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: F Xiao-Feng
authors.initials: FX
authors.lastname: Qin
authors.affiliation: CAS Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Chaoyang District, Beijing, China.
authors.forename: Hongyu
authors.initials: H
authors.lastname: Deng
authors.affiliation: 1] CAS Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Chaoyang District, Beijing, China [2] Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, CA 90095, USA.
authors.forename: Genhong
authors.initials: G
authors.lastname: Cheng
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D004261:DNA Replication / Q000187:drug effects; D057809:HEK293 Cells; D016174:Hepacivirus / Q000187:drug effects* / Q000378:metabolism*; D006526:Hepatitis C / Q000188:drug therapy / Q000378:metabolism / Q000821:virology; D006801:Humans; D007372:Interferons / Q000494:pharmacology*; D013250:Steroid Hydroxylases / Q000378:metabolism*; D017361:Viral Nonstructural Proteins / Q000378:metabolism; D053586:Virus Internalization; D014779:Virus Replication / Q000187:drug effects*; D012324:RNA-Dependent RNA Polymerase
chemical_list: D000998:Antiviral Agents; D007372:Interferons; D013250:Steroid Hydroxylases; D017361:Viral Nonstructural Proteins; C507384:cholesterol 25-hydroxylase; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase