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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.

Original publication

DOI

10.1016/j.chom.2013.02.006

Type

Journal article

Journal

Cell Host Microbe

Publication Date

13/03/2013

Volume

13

Pages

302 - 313

Keywords

Claudin-1, Hepacivirus, Hepatitis C, Humans, Protein Binding, Protein Multimerization, Proto-Oncogene Proteins p21(ras), Receptor, Epidermal Growth Factor, Signal Transduction, Tetraspanin 28, Tetraspanins, Virus Internalization