HRas signal transduction promotes hepatitis C virus cell entry by triggering assembly of the host tetraspanin receptor complex

Research output: Contribution to journalArticle

Authors

  • Laetitia Zona
  • Joachim Lupberger
  • Nazha Sidahmed-Adrar
  • Christine Thumann
  • Amy Barnes
  • Jonathan Florentin
  • Rajiv G Tawar
  • Fei Xiao
  • Marine Turek
  • Sarah C Durand
  • François H T Duong
  • Markus H Heim
  • François-Loïc Cosset
  • Ivan Hirsch
  • Didier Samuel
  • Laurent Brino
  • Mirjam B Zeisel
  • François Le Naour
  • Thomas F Baumert

Colleges, School and Institutes

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.

Details

Original languageEnglish
Pages (from-to)302-13
Number of pages12
JournalCell Host & Microbe
Volume13
Issue number3
Publication statusPublished - 13 Mar 2013

Keywords

  • Antigens, CD81, Claudin-1, Hepacivirus, Hepatitis C, Humans, Protein Binding, Protein Multimerization, Proto-Oncogene Proteins p21(ras), Receptor, Epidermal Growth Factor, Signal Transduction, Tetraspanins, Virus Internalization