title: Hepatitis C virus infection propagates through interactions between Syndecan-1 and CD81 and impacts the hepatocyte glycocalyx.
abstract: The hepatitis C virus (HCV) infects hepatocytes after binding to heparan sulfate proteoglycans, in particular Syndecan-1, followed by recognition of the tetraspanin CD81 and other receptors. Heparan sulfate proteoglycans are found in a specific microenvironment coating the hepatocyte surface called the glycocalyx and are receptors for extracellular matrix proteins, cytokines, growth factors, lipoproteins, and infectious agents. We investigated the mutual influence of HCV infection on the glycocalyx and revealed new links between Syndecan-1 and CD81. Hepatocyte infection by HCV was inhibited after knocking down Syndecan-1 or Xylosyltransferase 2, a key enzyme of Syndecan-1 biosynthesis. Simultaneous knockdown of Syndecan-1 and CD81 strongly inhibited infection, suggesting their cooperative action. At early infection stages, Syndecan-1 and virions colocalized at the plasma membrane and were internalized in endosomes. Direct interactions between Syndecan-1 and CD81 were revealed in primary and transformed hepatocytes by immunoprecipitation and proximity ligation assays. Expression of Syndecan-1 and Xylosyltransferase 2 was altered within days post-infection, and the remaining Syndecan-1 pool colocalized poorly with CD81. The data indicate a profound reshuffling of the hepatocyte glycocalyx during HCV infection, possibly required for establishing optimal conditions of viral propagation.
authors.affiliation: CRCL, Inserm U1052, CNRS 5286, Université Lyon 1, France.
authors.forename: Boyan
authors.initials: B
authors.lastname: Grigorov
authors.affiliation: CRCL, Inserm U1052, CNRS 5286, Université Lyon 1, France.
authors.forename: Emma
authors.initials: E
authors.lastname: Reungoat
authors.affiliation: CEA-iRTSV - LBGE - Gen&Chem, U1038 INSERM/CEA/UJF, CEA-Grenoble, France.
authors.forename: Alice
authors.initials: A
authors.lastname: Gentil Dit Maurin
authors.affiliation: UMR7565, Université de Lorraine, CNRS, Nancy, France.
authors.forename: Mihayl
authors.initials: M
authors.lastname: Varbanov
authors.affiliation: CRCL, Inserm U1052, CNRS 5286, Université Lyon 1, France.
authors.forename: Julie
authors.initials: J
authors.lastname: Blaising
authors.affiliation: CRCL, Inserm U1052, CNRS 5286, Université Lyon 1, France.
authors.forename: Maud
authors.initials: M
authors.lastname: Michelet
authors.affiliation: IGFL, ENS Lyon, CNRS UMR 5242, Université Lyon 1, France.
authors.forename: Rachel
authors.initials: R
authors.lastname: Manuel
authors.affiliation: CRCL, Inserm U1052, CNRS 5286, Université Lyon 1, France.
authors.forename: Romain
authors.initials: R
authors.lastname: Parent
authors.affiliation: CRCL, Inserm U1052, CNRS 5286, Université Lyon 1, France.
authors.forename: Birke
authors.initials: B
authors.lastname: Bartosch
authors.affiliation: CRCL, Inserm U1052, CNRS 5286, Université Lyon 1, France.
authors.forename: Fabien
authors.initials: F
authors.lastname: Zoulim
authors.affiliation: IGFL, ENS Lyon, CNRS UMR 5242, Université Lyon 1, France.
authors.forename: Florence
authors.initials: F
authors.lastname: Ruggiero
authors.affiliation: CRCL, Inserm U1052, CNRS 5286, Université Lyon 1, France.
authors.forename: Eve-Isabelle
authors.initials: EI
authors.lastname: Pécheur
mesh_terms: D002462:Cell Membrane / Q000378:metabolism; D011992:Endosomes / Q000378:metabolism; D019276:Glycocalyx / Q000378:metabolism*; D056945:Hep G2 Cells; D016174:Hepacivirus / Q000502:physiology*; D006526:Hepatitis C / Q000378:metabolism / Q000821:virology*; D022781:Hepatocytes / Q000378:metabolism / Q000821:virology*; D054884:Host-Pathogen Interactions; D006801:Humans; D010430:Pentosyltransferases / Q000378:metabolism; D021381:Protein Transport; D011991:Receptors, Virus / Q000378:metabolism; D053668:Syndecan-1 / Q000378:metabolism*; D060225:Tetraspanin 28 / Q000378:metabolism*; D014779:Virus Replication; D000097608:UDP Xylose-Protein Xylosyltransferase
chemical_list: D010430:Pentosyltransferases; D011991:Receptors, Virus; D053668:Syndecan-1; D060225:Tetraspanin 28; D000097608:UDP Xylose-Protein Xylosyltransferase; C554798:CD81 protein, human; C508241:SDC1 protein, human
keywords: glycocalyx; heparan sulfate proteoglycan; hepatitis C; hepatocyte; tetraspanin