title: Hepatitis C Virus Activates a Neuregulin-Driven Circuit to Modify Surface Expression of Growth Factor Receptors of the ErbB Family.
abstract: Recently, the epidermal growth factor (EGF) receptor (EGFR), a member of the ErbB receptor family, and its down-stream signalling have been identified as co-factors for HCV entry and replication. Since EGFR also functions as a heterodimer with other ErbB receptor family members, the subject of the present study was to investigate a possible viral interference with these cellular components. By using genotype 1b replicon cells as well as an infection-based system we found that while transcript and protein levels of EGFR and ErbB2 were up-regulated or unaffected, respectively, HCV induced a substantial reduction of ErbB3 and ErbB4 expression. Down-regulation of ErbB3 expression by HCV involves specificity protein (Sp)1-mediated induction of Neuregulin (NRG)1 expression as well as activation of Akt. Consistently, at transcript level disruption of ErbB3 expression by HCV can be prevented by knockdown of NRG1 or Sp1 expression, whereas reconstitution of ErbB3 protein levels requires inhibition of HCV-induced NRG1 expression and of Akt activity. Interestingly, the NRG1-mediated suppression of ErbB3 expression by HCV results in an enhanced expression of EGFR and ErbB2 on the cell surface, which can be mimicked by siRNA-mediated knockdown of ErbB3 expression. These data delineate a novel mechanism enabling HCV to sway the composition of the ErbB family members on the surface of its host cell by an NRG1-driven circuit and unravels a yet unknown cross-regulation between ErbB3 and the two other family members ErbB2 and EGFR. The shift of the receptor surface expression of the ErbB family towards enhanced expression of ErbB2 and EGFR triggered by HCV was found to promote viral RNA replication and infectivity. This suggests that HCV rearranges expression of ErbB family members to adapt the cellular environment to its requirements.
authors.affiliation: Department of Gastroenterology, Hepatology and Infectious Diseases, Medical Faculty, University Hospital, Heinrich Heine University of Düsseldorf, Moorenstrasse 5, 40225 Düsseldorf, Germany.
authors.forename: Sabine
authors.initials: S
authors.lastname: Stindt
authors.affiliation: Department of Gastroenterology, Hepatology and Infectious Diseases, Medical Faculty, University Hospital, Heinrich Heine University of Düsseldorf, Moorenstrasse 5, 40225 Düsseldorf, Germany.
authors.forename: Patricia
authors.initials: P
authors.lastname: Cebula
authors.affiliation: Department of Gastroenterology, Hepatology and Infectious Diseases, Medical Faculty, University Hospital, Heinrich Heine University of Düsseldorf, Moorenstrasse 5, 40225 Düsseldorf, Germany.
authors.forename: Ute
authors.initials: U
authors.lastname: Albrecht
authors.affiliation: Department of Gastroenterology, Hepatology and Infectious Diseases, Medical Faculty, University Hospital, Heinrich Heine University of Düsseldorf, Moorenstrasse 5, 40225 Düsseldorf, Germany.
authors.forename: Verena
authors.initials: V
authors.lastname: Keitel
authors.affiliation: Department of General, Visceral, and Pediatric Surgery, Medical Faculty, University Hospital, Heinrich Heine University of Düsseldorf, Moorenstrasse 5, 40225 Düsseldorf, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Schulte am Esch
authors.affiliation: Department of General, Visceral, and Pediatric Surgery, Medical Faculty, University Hospital, Heinrich Heine University of Düsseldorf, Moorenstrasse 5, 40225 Düsseldorf, Germany.
authors.forename: Wolfram T
authors.initials: WT
authors.lastname: Knoefel
authors.affiliation: Department for Infectious Diseases, Molecular Virology, Heidelberg University, Heidelberg, Germany.|Division for Virus-Associated Carcinogenesis, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Ralf
authors.initials: R
authors.lastname: Bartenschlager
authors.affiliation: Department of Gastroenterology, Hepatology and Infectious Diseases, Medical Faculty, University Hospital, Heinrich Heine University of Düsseldorf, Moorenstrasse 5, 40225 Düsseldorf, Germany.
authors.forename: Dieter
authors.initials: D
authors.lastname: Häussinger
authors.affiliation: Department of Gastroenterology, Hepatology and Infectious Diseases, Medical Faculty, University Hospital, Heinrich Heine University of Düsseldorf, Moorenstrasse 5, 40225 Düsseldorf, Germany.
authors.forename: Johannes G
authors.initials: JG
authors.lastname: Bode
mesh_terms: D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D004121:Dimethyl Sulfoxide / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D066260:Epiregulin / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D016174:Hepacivirus / Q000187:drug effects / Q000378:metabolism* / Q000472:pathogenicity; D006801:Humans; D008024:Ligands; D008954:Models, Biological; D020890:Neuregulin-1 / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016329:Sp1 Transcription Factor / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects; D014779:Virus Replication / Q000187:drug effects
chemical_list: D066260:Epiregulin; D008024:Ligands; C094131:NRG1 protein, human; D020890:Neuregulin-1; D012333:RNA, Messenger; D016329:Sp1 Transcription Factor; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt; D004121:Dimethyl Sulfoxide