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Functional microRNA screen uncovers O-linked N-acetylglucosamine transferase as a host factor modulating hepatitis C virus morphogenesis and infectivity.

Authors
  • Herzog, Katharina1, 2
  • Bandiera, Simonetta1, 2
  • Pernot, Sophie1, 2
  • Fauvelle, Catherine1, 2
  • Jühling, Frank1, 2
  • Weiss, Amélie2, 3, 4, 5
  • Bull, Anne6
  • Durand, Sarah C1, 2
  • Chane-Woon-Ming, Béatrice2, 7
  • Pfeffer, Sébastien2, 7
  • Mercey, Marion8
  • Lerat, Hervé8
  • Meunier, Jean-Christophe6
  • Raffelsberger, Wolfgang2, 3, 4, 5
  • Brino, Laurent2, 3, 4, 5
  • Baumert, Thomas F1, 2, 9
  • Zeisel, Mirjam B1, 2, 10
  • 1 Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg, France. , (France)
  • 2 University of Strasbourg, Strasbourg, France. , (France)
  • 3 Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France. , (France)
  • 4 CNRS, UMR7104, Illkirch, France. , (France)
  • 5 Inserm, U1258, Illkirch, France. , (France)
  • 6 Inserm, U1259, Faculté de Médecine, Université François Rabelais and CHRU de Tours, Tours, France. , (France)
  • 7 Architecture et Réactivité de l'ARN - UPR 9002, Institut de Biologie Moléculaire et Cellulaire du CNRS, Strasbourg, France. , (France)
  • 8 Institute for Applied Biosciences, Centre de Recherche UGA, Inserm U1209 - CNRS 5309, Grenoble, France. , (France)
  • 9 Institut Hospitalo-Universitaire, Pôle Hépato-digestif, Hôpitaux Universitaires de Strasbourg, Strasbourg, France. , (France)
  • 10 Inserm, U1052, CNRS UMR 5286, Centre Léon Bérard (CLB), Cancer Research Center of Lyon (CRCL), Université de Lyon (UCBL), Lyon, France. , (France)
Type
Published Article
Journal
Gut
Publisher
BMJ
Publication Date
Feb 01, 2020
Volume
69
Issue
2
Pages
380–392
Identifiers
DOI: 10.1136/gutjnl-2018-317423
PMID: 31076402
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Infection of human hepatocytes by the hepatitis C virus (HCV) is a multistep process involving both viral and host factors. microRNAs (miRNAs) are small non-coding RNAs that post-transcriptionally regulate gene expression. Given that miRNAs were indicated to regulate between 30% and 75% of all human genes, we aimed to investigate the functional and regulatory role of miRNAs for the HCV life cycle. To systematically reveal human miRNAs affecting the HCV life cycle, we performed a two-step functional high-throughput miRNA mimic screen in Huh7.5.1 cells infected with recombinant cell culture-derived HCV. miRNA targeting was then assessed using a combination of computational and functional approaches. We uncovered miR-501-3p and miR-619-3p as novel modulators of HCV assembly/release. We discovered that these miRNAs regulate O-linked N-acetylglucosamine (O-GlcNAc) transferase (OGT) protein expression and identified OGT and O-GlcNAcylation as regulators of HCV morphogenesis and infectivity. Furthermore, increased OGT expression in patient-derived liver tissue was associated with HCV-induced liver disease and cancer. miR-501-3p and miR-619-3p and their target OGT are previously undiscovered regulatory host factors for HCV assembly and infectivity. In addition to its effect on HCV morphogenesis, OGT may play a role in HCV-induced liver disease and hepatocarcinogenesis. © Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.

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