title: Solute Carrier NTCP Regulates Innate Antiviral Immune Responses Targeting Hepatitis C Virus Infection of Hepatocytes.
abstract: Chronic hepatitis B, C, and D virus (HBV, HCV, and HDV) infections are the leading causes of liver disease and cancer worldwide. Recently, the solute carrier and sodium taurocholate co-transporter NTCP has been identified as a receptor for HBV and HDV. Here, we uncover NTCP as a host factor regulating HCV infection. Using gain- and loss-of-function studies, we show that NTCP mediates HCV infection of hepatocytes and is relevant for cell-to-cell transmission. NTCP regulates HCV infection by augmenting the bile-acid-mediated repression of interferon-stimulated genes (ISGs), including IFITM3. In conclusion, our results uncover NTCP as a mediator of innate antiviral immune responses in the liver, and they establish a role for NTCP in the infection process of multiple viruses via distinct mechanisms. Collectively, our findings suggest a role for solute carriers in the regulation of innate antiviral responses, and they have potential implications for virus-host interactions and antiviral therapies.
authors: INSERM, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, 67000 Strasbourg, France; Université de Strasbourg, 67000 Strasbourg, France.
authors: Eloi R
authors: ER
authors: Verrier
authors: INSERM, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, 67000 Strasbourg, France; Université de Strasbourg, 67000 Strasbourg, France.
authors: Che C
authors: CC
authors: Colpitts
authors: INSERM, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, 67000 Strasbourg, France; Université de Strasbourg, 67000 Strasbourg, France.
authors: Charlotte
authors: C
authors: Bach
authors: INSERM, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, 67000 Strasbourg, France; Université de Strasbourg, 67000 Strasbourg, France.
authors: Laura
authors: L
authors: Heydmann
authors: INSERM, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, 67000 Strasbourg, France; Université de Strasbourg, 67000 Strasbourg, France.
authors: Laetitia
authors: L
authors: Zona
authors: INSERM, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, 67000 Strasbourg, France; Université de Strasbourg, 67000 Strasbourg, France.
authors: Fei
authors: F
authors: Xiao
authors: INSERM, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, 67000 Strasbourg, France; Université de Strasbourg, 67000 Strasbourg, France.
authors: Christine
authors: C
authors: Thumann
authors: INSERM, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, 67000 Strasbourg, France; Université de Strasbourg, 67000 Strasbourg, France.
authors: Emilie
authors: E
authors: Crouchet
authors: INSERM, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, 67000 Strasbourg, France; Université de Strasbourg, 67000 Strasbourg, France.
authors: Raphaël
authors: R
authors: Gaudin
authors: INTS, Laboratoire de Virologie Moléculaire, 75015 Paris, France.
authors: Camille
authors: C
authors: Sureau
authors: CIRI-International Center for Infectiology Research, 69364 Lyon Cedex 07, France; INSERM, U1111, 69007 Lyon, France; Ecole Normale Supérieure, 69007 Lyon, France; Centre National de la Recherche Scientifique (CNRS) UMR 5308, 69007 Lyon, France; LabEx Ecofect, University of Lyon, 69007 Lyon, France.
authors: François-Loïc
authors: FL
authors: Cosset
authors: Centre for Human Virology, University of Birmingham, Birmingham, UK; NIHR Liver Biomedical Research Unit, University of Birmingham, Birmingham, UK.
authors: Jane A
authors: JA
authors: McKeating
authors: INSERM, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, 67000 Strasbourg, France; Université de Strasbourg, 67000 Strasbourg, France; Institut Hospitalo-universitaire, Pôle Hépato-digestif, Nouvel Hôpital Civil, 67000 Strasbourg, France.
authors: Patrick
authors: P
authors: Pessaux
authors: Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Liver Cancer Program, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors: Yujin
authors: Y
authors: Hoshida
authors: INSERM, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, 67000 Strasbourg, France; Université de Strasbourg, 67000 Strasbourg, France.
authors: Catherine
authors: C
authors: Schuster
authors: INSERM, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, 67000 Strasbourg, France; Université de Strasbourg, 67000 Strasbourg, France. Electronic address: mirjam.zeisel@unistra.fr.
authors: Mirjam B
authors: MB
authors: Zeisel
authors: INSERM, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, 67000 Strasbourg, France; Université de Strasbourg, 67000 Strasbourg, France; Institut Hospitalo-universitaire, Pôle Hépato-digestif, Nouvel Hôpital Civil, 67000 Strasbourg, France. Electronic address: thomas.baumert@unistra.fr.
authors: Thomas F
authors: TF
authors: Baumert
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology*; D001647:Bile Acids and Salts / Q000378:metabolism; D001692:Biological Transport; D045744:Cell Line, Tumor; D005786:Gene Expression Regulation / Q000187:drug effects; D020868:Gene Silencing / Q000187:drug effects; D016174:Hepacivirus / Q000187:drug effects / Q000502:physiology*; D006514:Hepatitis B Surface Antigens / Q000378:metabolism; D006515:Hepatitis B virus / Q000502:physiology; D006526:Hepatitis C / Q000378:metabolism* / Q000473:pathology / Q000821:virology*; D003698:Hepatitis Delta Virus / Q000502:physiology; D022781:Hepatocytes / Q000187:drug effects / Q000473:pathology / Q000821:virology*; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects; D007372:Interferons / Q000494:pharmacology; D029363:Organic Anion Transporters, Sodium-Dependent / Q000378:metabolism*; D010455:Peptides / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D011498:Protein Precursors / Q000378:metabolism; D027981:Symporters / Q000378:metabolism*; D053586:Virus Internalization / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D001647:Bile Acids and Salts; D006514:Hepatitis B Surface Antigens; D029363:Organic Anion Transporters, Sodium-Dependent; D010455:Peptides; D011498:Protein Precursors; D027981:Symporters; C050806:presurface protein 1, hepatitis B surface antigen; C071908:sodium-bile acid cotransporter; D007372:Interferons
keywords: NTCP; antiviral therapy; hepatitis B virus; hepatitis C virus; hepatitis D virus; host factor; innate immune responses; signaling; solute carrier; viral entry