title: A telomerase-derived peptide regulates reactive oxygen species and hepatitis C virus RNA replication in HCV-infected cells via heat shock protein 90.
abstract: GV1001, a synthetic peptide derived from human telomerase, has a range of diverse biological activities, including an antioxidant function. Here, we investigated the role of GV1001 in hepatitis C virus (HCV)-infected Huh7.5 (JFH-1) cells. We showed that GV1001 inhibited the production of ROS with decreased MAP kinase signaling. Interestingly, GV1001 lost its antioxidant activity as ROS levels decreased, resulting in a reduction in extracellular heat shock protein 90 (eHSP90) as low-density lipoprotein receptor-related protein 1 (LRP1) was blocked or knocked-down. GV1001 binds to eHSP90 and is delivered into the cell by endocytosis via LRP1. Endocytosed GV1001 finally suppressed ROS generation, presumably by hindering the interaction between eHSP90 and NADPH oxidase (NOX). Importantly, GV1001 suppressed HCV RNA replication in JFH-1 cells by inhibiting the binding of HSP90 to FKBP8, a member of the FK506-binding protein family. We also found that HSP90 expression was high in HCV-infected hepatocytes. Therefore, our data suggest that GV1001 may be a good therapeutic agent by controlling HCV RNA replication, as well as by preferentially targeting cells under conditions of oxidative stress.
authors.affiliation: Department of Microbiology and Immunology, Seoul National University College of Medicine, Seoul 03080, Republic of Korea.
authors.forename: Seoung-Ae
authors.initials: SA
authors.lastname: Lee
authors.affiliation: Department of Anatomy and Cell Biology, Seoul National University College of Medicine, Seoul 03080, Republic of Korea; Department of Biomedical Laboratory Science, College of Health Science, Cheongju University, Cheongju 28503, Republic of Korea.
authors.forename: Jinhee
authors.initials: J
authors.lastname: Kim
authors.affiliation: Department of Anatomy and Cell Biology, Seoul National University College of Medicine, Seoul 03080, Republic of Korea.
authors.forename: Jihyun
authors.initials: J
authors.lastname: Sim
authors.affiliation: Digestive Disease Center and Research Institute, SoonChunHyang University Bucheon Hospital, Bucheon 14584, Republic of Korea.
authors.forename: Sang-Gyune
authors.initials: SG
authors.lastname: Kim
authors.affiliation: Department of Microbiology and Immunology, Seoul National University College of Medicine, Seoul 03080, Republic of Korea; Cancer Research Institute, Seoul National University College of Medicine, Seoul 03080, Republic of Korea; Medical Research Institute for Infectious Diseases, Seoul National University College of Medicine, Seoul 03080, Republic of Korea.
authors.forename: Yoon-Hoh
authors.initials: YH
authors.lastname: Kook
authors.affiliation: Department of Microbiology and Immunology, Seoul National University College of Medicine, Seoul 03080, Republic of Korea; Cancer Research Institute, Seoul National University College of Medicine, Seoul 03080, Republic of Korea; Medical Research Institute for Infectious Diseases, Seoul National University College of Medicine, Seoul 03080, Republic of Korea; Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 03080, Republic of Korea.
authors.forename: Chung-Gyu
authors.initials: CG
authors.lastname: Park
authors.affiliation: Medical Research Institute for Infectious Diseases, Seoul National University College of Medicine, Seoul 03080, Republic of Korea; Department of Anatomy and Cell Biology, Seoul National University College of Medicine, Seoul 03080, Republic of Korea; Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 03080, Republic of Korea. Electronic address: hangrae2@snu.ac.kr.
authors.forename: Hang-Rae
authors.initials: HR
authors.lastname: Kim
authors.affiliation: Department of Microbiology and Immunology, Seoul National University College of Medicine, Seoul 03080, Republic of Korea; Cancer Research Institute, Seoul National University College of Medicine, Seoul 03080, Republic of Korea; Liver Research Institute, Seoul National University College of Medicine, Seoul 03080, Republic of Korea; Medical Research Institute for Infectious Diseases, Seoul National University College of Medicine, Seoul 03080, Republic of Korea; Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 03080, Republic of Korea. Electronic address: kbumjoon@snu.ac.kr.
authors.forename: Bum-Joon
authors.initials: BJ
authors.lastname: Kim
mesh_terms: D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000502:physiology; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism*; D016174:Hepacivirus / Q000502:physiology*; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism / Q000821:virology*; D006801:Humans; D010446:Peptide Fragments / Q000008:administration & dosage*; D012367:RNA, Viral / Q000235:genetics*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D019098:Telomerase / Q000008:administration & dosage*; D014779:Virus Replication / Q000187:drug effects / Q000235:genetics
chemical_list: D018841:HSP90 Heat-Shock Proteins; D010446:Peptide Fragments; D012367:RNA, Viral; D017382:Reactive Oxygen Species; C514987:GV1001 peptide; D019098:Telomerase
keywords: Antioxidant; GV1001; Heat shock protein 90; Hepatitis C virus; Low-density lipoprotein receptor-related protein 1