title: HRas signal transduction promotes hepatitis C virus cell entry by triggering assembly of the host tetraspanin receptor complex.
abstract: Hepatitis C virus (HCV) entry is dependent on coreceptor complex formation between the tetraspanin superfamily member CD81 and the tight junction protein claudin-1 (CLDN1) on the host cell membrane. The receptor tyrosine kinase EGFR acts as a cofactor for HCV entry by promoting CD81-CLDN1 complex formation via unknown mechanisms. We identify the GTPase HRas, activated downstream of EGFR signaling, as a key host signal transducer for EGFR-mediated HCV entry. Proteomic analysis revealed that HRas associates with tetraspanin CD81, CLDN1, and the previously unrecognized HCV entry cofactors integrin β1 and Ras-related protein Rap2B in hepatocyte membranes. HRas signaling is required for lateral membrane diffusion of CD81, which enables tetraspanin receptor complex assembly. HRas was also found to be relevant for entry of other viruses, including influenza. Our data demonstrate that viruses exploit HRas signaling for cellular entry by compartmentalization of entry factors and receptor trafficking.
authors.affiliation: Inserm, U1110, Institut de Virologie, 67000 Strasbourg, France.
authors.forename: Laetitia
authors.initials: L
authors.lastname: Zona
authors.forename: Joachim
authors.initials: J
authors.lastname: Lupberger
authors.forename: Nazha
authors.initials: N
authors.lastname: Sidahmed-Adrar
authors.forename: Christine
authors.initials: C
authors.lastname: Thumann
authors.forename: Helen J
authors.initials: HJ
authors.lastname: Harris
authors.forename: Amy
authors.initials: A
authors.lastname: Barnes
authors.forename: Jonathan
authors.initials: J
authors.lastname: Florentin
authors.forename: Rajiv G
authors.initials: RG
authors.lastname: Tawar
authors.forename: Fei
authors.initials: F
authors.lastname: Xiao
authors.forename: Marine
authors.initials: M
authors.lastname: Turek
authors.forename: Sarah C
authors.initials: SC
authors.lastname: Durand
authors.forename: François H T
authors.initials: FH
authors.lastname: Duong
authors.forename: Markus H
authors.initials: MH
authors.lastname: Heim
authors.forename: François-Loïc
authors.initials: FL
authors.lastname: Cosset
authors.forename: Ivan
authors.initials: I
authors.lastname: Hirsch
authors.forename: Didier
authors.initials: D
authors.lastname: Samuel
authors.forename: Laurent
authors.initials: L
authors.lastname: Brino
authors.forename: Mirjam B
authors.initials: MB
authors.lastname: Zeisel
authors.forename: François
authors.initials: F
authors.lastname: Le Naour
authors.forename: Jane A
authors.initials: JA
authors.lastname: McKeating
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Baumert
mesh_terms: D062445:Claudin-1 / Q000737:chemistry / Q000378:metabolism*; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D016174:Hepacivirus / Q000502:physiology*; D006526:Hepatitis C / Q000235:genetics / Q000378:metabolism* / Q000821:virology; D006801:Humans; D011485:Protein Binding; D055503:Protein Multimerization; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D060225:Tetraspanin 28 / Q000737:chemistry / Q000378:metabolism*; D059470:Tetraspanins / Q000235:genetics / Q000378:metabolism; D053586:Virus Internalization
chemical_list: C568108:CLDN1 protein, human; D062445:Claudin-1; D060225:Tetraspanin 28; D059470:Tetraspanins; C512478:EGFR protein, human; D066246:ErbB Receptors; C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras)