title: Involvement of FKBP6 in hepatitis C virus replication.
abstract: The chaperone system is known to be exploited by viruses for their replication. In the present study, we identified the cochaperone FKBP6 as a host factor required for hepatitis C virus (HCV) replication. FKBP6 is a peptidyl prolyl cis-trans isomerase with three domains of the tetratricopeptide repeat (TPR), but lacks FK-506 binding ability. FKBP6 interacted with HCV nonstructural protein 5A (NS5A) and also formed a complex with FKBP6 itself or FKBP8, which is known to be critical for HCV replication. The Val(121) of NS5A and TPR domains of FKBP6 were responsible for the interaction between NS5A and FKBP6. FKBP6 was colocalized with NS5A, FKBP8, and double-stranded RNA in HCV-infected cells. HCV replication was completely suppressed in FKBP6-knockout hepatoma cell lines, while the expression of FKBP6 restored HCV replication in FKBP6-knockout cells. A treatment with the FKBP8 inhibitor N-(N', N'-dimethylcarboxamidomethyl)cycloheximide impaired the formation of a homo- or hetero-complex consisting of FKBP6 and/or FKBP8, and suppressed HCV replication. HCV infection promoted the expression of FKBP6, but not that of FKBP8, in cultured cells and human liver tissue. These results indicate that FKBP6 is an HCV-induced host factor that supports viral replication in cooperation with NS5A.
authors.affiliation: Department of Microbiology, Faculty of Medicine, University of Yamanashi, Chuo-shi, Yamanashi 409-3898, Japan.
authors.forename: Hirotake
authors.initials: H
authors.lastname: Kasai
authors.affiliation: Faculty of Life and Environmental Sciences, University of Yamanashi, Kofu-shi, Yamanashi 400-8510, Japan.
authors.forename: Kunihiro
authors.initials: K
authors.lastname: Kawakami
authors.affiliation: Institute of Medical Chemistry, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 142-8501, Japan.
authors.forename: Hiromasa
authors.initials: H
authors.lastname: Yokoe
authors.affiliation: Department of Anatomy and Cell Biology, Division of Medicine, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Chuo-shi, Yamanashi 409-3898, Japan.
authors.forename: Kentaro
authors.initials: K
authors.lastname: Yoshimura
authors.affiliation: Department of First Surgery, Faculty of Medicine, University of Yamanashi, Chuo-shi, Yamanashi 409-3898, Japan.
authors.forename: Masanori
authors.initials: M
authors.lastname: Matsuda
authors.affiliation: Department of Microbiology, Faculty of Medicine, University of Yamanashi, Chuo-shi, Yamanashi 409-3898, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Yasumoto
authors.affiliation: First Department of Internal Medicine, Faculty of Medicine, University of Yamanashi, Chuo-shi, Yamanashi 409-3898, Japan.
authors.forename: Shinya
authors.initials: S
authors.lastname: Maekawa
authors.affiliation: Department of Microbiology, Faculty of Medicine, University of Yamanashi, Chuo-shi, Yamanashi 409-3898, Japan.
authors.forename: Atsuya
authors.initials: A
authors.lastname: Yamashita
authors.affiliation: Department of Microbiology, Faculty of Medicine, University of Yamanashi, Chuo-shi, Yamanashi 409-3898, Japan.
authors.forename: Tomohisa
authors.initials: T
authors.lastname: Tanaka
authors.affiliation: Department of Tumor Virology, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University, Okayama, Okayama 700-8530, Japan.
authors.forename: Masanori
authors.initials: M
authors.lastname: Ikeda
authors.affiliation: Department of Tumor Virology, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University, Okayama, Okayama 700-8530, Japan.
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Kato
authors.affiliation: Department of Molecular Virology, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 565-0871, Japan.
authors.forename: Toru
authors.initials: T
authors.lastname: Okamoto
authors.affiliation: Department of Molecular Virology, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 565-0871, Japan.
authors.forename: Yoshiharu
authors.initials: Y
authors.lastname: Matsuura
authors.affiliation: Department of Gastroenterology and Hepatology, Hokkaido University Graduate School of Medicine, Sapporo, Hokkaido 060-8638, Japan.
authors.forename: Naoya
authors.initials: N
authors.lastname: Sakamoto
authors.affiliation: First Department of Internal Medicine, Faculty of Medicine, University of Yamanashi, Chuo-shi, Yamanashi 409-3898, Japan.
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Enomoto
authors.affiliation: Department of Anatomy and Cell Biology, Division of Medicine, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Chuo-shi, Yamanashi 409-3898, Japan.
authors.forename: Sen
authors.initials: S
authors.lastname: Takeda
authors.affiliation: Department of First Surgery, Faculty of Medicine, University of Yamanashi, Chuo-shi, Yamanashi 409-3898, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Fujii
authors.affiliation: Institute of Medical Chemistry, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 142-8501, Japan.
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Tsubuki
authors.affiliation: Faculty of Life and Environmental Sciences, University of Yamanashi, Kofu-shi, Yamanashi 400-8510, Japan.
authors.forename: Masami
authors.initials: M
authors.lastname: Kusunoki
authors.affiliation: Department of Microbiology, Faculty of Medicine, University of Yamanashi, Chuo-shi, Yamanashi 409-3898, Japan.
authors.forename: Kohji
authors.initials: K
authors.lastname: Moriishi
mesh_terms: D064113:CRISPR-Cas Systems / Q000235:genetics; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003513:Cycloheximide / Q000031:analogs & derivatives / Q000494:pharmacology; D057809:HEK293 Cells; D016174:Hepacivirus / Q000502:physiology*; D006801:Humans; D008856:Microscopy, Fluorescence; D054730:Protein Interaction Domains and Motifs; D055503:Protein Multimerization / Q000187:drug effects; D034622:RNA Interference; D012330:RNA, Double-Stranded / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D022021:Tacrolimus Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D017361:Viral Nonstructural Proteins / Q000737:chemistry / Q000378:metabolism*; D014779:Virus Replication; D012324:RNA-Dependent RNA Polymerase
chemical_list: D003513:Cycloheximide; D012330:RNA, Double-Stranded; D034741:RNA, Small Interfering; D022021:Tacrolimus Binding Proteins; D017361:Viral Nonstructural Proteins; C115725:FKBP6 protein, human; C471205:FKBP8 protein, human; C511362:N-(N',N'-dimethylcarboxamidomethyl)cycloheximide; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase