title: MCPIP1 suppresses hepatitis C virus replication and negatively regulates virus-induced proinflammatory cytokine responses.
abstract: Human MCP-1-induced protein 1 (MCPIP1, also known as ZC3H12A and Regnase-1) plays important roles in negatively regulating the cellular inflammatory response. Recently, we found that as an RNase, MCPIP1 has broad-spectrum antiviral effects by targeting viral RNA. In this study, we demonstrated that MCPIP1 expression was induced by hepatitis C virus (HCV) infection in Huh7.5 hepatoma cells. MCPIP1 expression was higher in liver tissue from patients with chronic HCV infection compared with those without chronic HCV infection. Knockdown of MCPIP1 increased HCV replication and HCV-mediated expression of proinflammatory cytokines, such as TNF-α, IL-6, and MCP-1. However, overexpression of MCPIP1 significantly inhibited HCV replication and HCV-mediated expression of proinflammatory cytokines. Various mutants of functional domains of MCPIP1 showed disruption of the RNA binding and oligomerization abilities, as well as RNase activity, but not deubiquitinase activity, which impaired the inhibitory activity against HCV replication. On immunocytochemistry, MCPIP1 colocalized with HCV RNA. Use of a replication-defective HCV John Cunningham 1/AAG mutant and in vitro RNA cleavage assay demonstrated that MCPIP1 could directly degrade HCV RNA. MCPIP1 may suppress HCV replication and HCV-mediated proinflammatory responses with infection, which might contribute to the regulation of host defense against the infection and virus-induced inflammation.
authors.affiliation: Department of General Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan; Department of Primary Care Medicine, Taipei Medical University Hospital, Taipei 11031, Taiwan;
authors.forename: Ren-Jye
authors.initials: RJ
authors.lastname: Lin
authors.affiliation: Department of Pathology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan; Department of Pathology, Taipei Medical University Hospital, Taipei 11031, Taiwan;
authors.forename: Jan-Show
authors.initials: JS
authors.lastname: Chu
authors.affiliation: Institute of Molecular Biology, Academia Sinica, Taipei 11529, Taiwan;
authors.forename: Hsu-Ling
authors.initials: HL
authors.lastname: Chien
authors.affiliation: Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan; Center of Infectious Disease and Signaling Research, National Cheng Kung University, Tainan 70101, Taiwan;
authors.forename: Chung-Hsin
authors.initials: CH
authors.lastname: Tseng
authors.affiliation: School of Medical Laboratory Science and Biotechnology, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan;
authors.forename: Pin-Chen
authors.initials: PC
authors.lastname: Ko
authors.affiliation: School of Medical Laboratory Science and Biotechnology, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan;
authors.forename: Yung-Yu
authors.initials: YY
authors.lastname: Mei
authors.affiliation: Graduate Institute of Life Sciences, National Defense Medical Center, Taipei 11490, Taiwan; and.
authors.forename: Wei-Chun
authors.initials: WC
authors.lastname: Tang
authors.affiliation: Graduate Institute of Life Sciences, National Defense Medical Center, Taipei 11490, Taiwan; and.
authors.forename: Yu-Ting
authors.initials: YT
authors.lastname: Kao
authors.affiliation: School of Medical Laboratory Science and Biotechnology, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan;
authors.forename: Hui-Ying
authors.initials: HY
authors.lastname: Cheng
authors.affiliation: School of Medical Laboratory Science and Biotechnology, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan; Traditional Herbal Medicine Research Center, Taipei Medical University Hospital, Taipei 11031, Taiwan sylin@tmu.edu.tw ycliang@tmu.edu.tw.
authors.forename: Yu-Chih
authors.initials: YC
authors.lastname: Liang
authors.affiliation: Department of General Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan; Department of Primary Care Medicine, Taipei Medical University Hospital, Taipei 11031, Taiwan; sylin@tmu.edu.tw ycliang@tmu.edu.tw.
authors.forename: Shyr-Yi
authors.initials: SY
authors.lastname: Lin
mesh_terms: D045744:Cell Line, Tumor; D018932:Chemokine CCL2 / Q000096:biosynthesis; D057809:HEK293 Cells; D016174:Hepacivirus / Q000235:genetics / Q000502:physiology*; D019698:Hepatitis C, Chronic / Q000276:immunology* / Q000473:pathology / Q000821:virology; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis; D008099:Liver / Q000276:immunology / Q000473:pathology / Q000821:virology; D009154:Mutation; D017434:Protein Structure, Tertiary; D034622:RNA Interference; D034741:RNA, Small Interfering; D012367:RNA, Viral / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000235:genetics; D012260:Ribonucleases; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D064570:Ubiquitin-Specific Proteases; D014779:Virus Replication
chemical_list: C111835:CCL2 protein, human; D018932:Chemokine CCL2; C508600:IL6 protein, human; D015850:Interleukin-6; D034741:RNA, Small Interfering; D012367:RNA, Viral; D016601:RNA-Binding Proteins; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D012260:Ribonucleases; C510646:ZC3H12A protein, human; D064570:Ubiquitin-Specific Proteases