title: miR-122 stimulates hepatitis C virus RNA synthesis by altering the balance of viral RNAs engaged in replication versus translation.
abstract: The liver-specific microRNA, miR-122, stabilizes hepatitis C virus (HCV) RNA genomes by recruiting host argonaute 2 (AGO2) to the 5' end and preventing decay mediated by exonuclease Xrn1. However, HCV replication requires miR-122 in Xrn1-depleted cells, indicating additional functions. We show that miR-122 enhances HCV RNA levels by altering the fraction of HCV genomes available for RNA synthesis. Exogenous miR-122 increases viral RNA and protein levels in Xrn1-depleted cells, with enhanced RNA synthesis occurring before heightened protein synthesis. Inhibiting protein translation with puromycin blocks miR-122-mediated increases in RNA synthesis, but independently enhances RNA synthesis by releasing ribosomes from viral genomes. Additionally, miR-122 reduces the fraction of viral genomes engaged in protein translation. Depleting AGO2 or PCBP2, which binds HCV RNA in competition with miR-122 and promotes translation, eliminates miR-122 stimulation of RNA synthesis. Thus, by displacing PCBP2, miR-122 reduces HCV genomes engaged in translation while increasing the fraction available for RNA synthesis.
authors: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27517, USA; Department of Virology II, National Institute of Infectious Diseases, Toyama 1-23-1, Shinjuku-ku, Tokyo 162-8640, Japan.
authors: Takahiro
authors: T
authors: Masaki
authors: Department of Microbiology & Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27517, USA.
authors: Kyle C
authors: KC
authors: Arend
authors: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27517, USA.
authors: You
authors: Y
authors: Li
authors: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27517, USA.
authors: Daisuke
authors: D
authors: Yamane
authors: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27517, USA; Division of Infectious Diseases, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27517, USA.
authors: David R
authors: DR
authors: McGivern
authors: Department of Virology II, National Institute of Infectious Diseases, Toyama 1-23-1, Shinjuku-ku, Tokyo 162-8640, Japan.
authors: Takanobu
authors: T
authors: Kato
authors: Department of Virology II, National Institute of Infectious Diseases, Toyama 1-23-1, Shinjuku-ku, Tokyo 162-8640, Japan.
authors: Takaji
authors: T
authors: Wakita
authors: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27517, USA; Department of Microbiology & Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27517, USA.
authors: Nathaniel J
authors: NJ
authors: Moorman
authors: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27517, USA; Department of Microbiology & Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27517, USA; Division of Infectious Diseases, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27517, USA. Electronic address: smlemon@med.unc.edu.
authors: Stanley M
authors: SM
authors: Lemon
mesh_terms: D002460:Cell Line; D015967:Gene Expression Regulation, Viral; D016174:Hepacivirus / Q000502:physiology*; D054884:Host-Pathogen Interactions; D006801:Humans; D035683:MicroRNAs / Q000378:metabolism*; D014176:Protein Biosynthesis; D012367:RNA, Viral / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000037:antagonists & inhibitors; D014158:Transcription, Genetic; D014779:Virus Replication
chemical_list: C531907:MIRN122 microRNA, human; D035683:MicroRNAs; C501903:PCBP2 protein, human; D012367:RNA, Viral; D016601:RNA-Binding Proteins