title: Hepatitis C virus impairs the induction of cytoprotective Nrf2 target genes by delocalization of small Maf proteins.
abstract: The expression of a variety of cytoprotective genes is regulated by short cis-acting elements in their promoters, called antioxidant response elements (AREs). A central regulator of ARE-mediated gene expression is the NF-E2-related factor 2 (Nrf2). Nrf2/ARE-regulated genes are crucial for the maintenance of cellular integrity. Hepatitis C virus inhibits the induction of ARE-regulated genes, but neither induction nor inhibition of ARE-regulated gene expression affects HCV replication directly. In HCV-replicating cells the core protein triggers the delocalization of sMaf proteins from the nucleus to the replicon complex. Here sMafs bind to NS3. The extranuclear sMaf proteins prevent Nrf2 from entry in the nucleus and thereby inhibit the induction of Nrf2/ARE-regulated genes. This results in the decreased expression of cytoprotective genes. Consistent with this finding, the elimination of ROI is impaired in HCV-replicating cells as demonstrated by elevated protein oxidation or 8-OH-dG formation, reflecting DNA damage. In conclusion, these data identified a novel mechanism of Nrf2 regulation and suggest that the HCV-dependent inhibition of Nrf2/ARE-regulated genes confers to the HCV-associated pathogenesis by elevation of intracellular ROI that affect integrity of the host genome and regenerative processes.
authors.affiliation: Institute of Infection Medicine, Molecular Medical Virology, University of Kiel, D-24105 Kiel, Germany.
authors.forename: Monica
authors.initials: M
authors.lastname: Carvajal-Yepes
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Himmelsbach
authors.forename: Stephanie
authors.initials: S
authors.lastname: Schaedler
authors.forename: Daniela
authors.initials: D
authors.lastname: Ploen
authors.forename: Janis
authors.initials: J
authors.lastname: Krause
authors.forename: Leopold
authors.initials: L
authors.lastname: Ludwig
authors.forename: Thomas
authors.initials: T
authors.lastname: Weiss
authors.forename: Karin
authors.initials: K
authors.lastname: Klingel
authors.forename: Eberhard
authors.initials: E
authors.lastname: Hildt
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000235:genetics; D000975:Antioxidants / Q000378:metabolism; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism* / Q000821:virology; D016174:Hepacivirus / Q000502:physiology*; D006801:Humans; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D010084:Oxidation-Reduction; D011485:Protein Binding; D051257:Proto-Oncogene Proteins c-maf / Q000235:genetics / Q000378:metabolism*; D020218:Response Elements; D014758:Viral Core Proteins / Q000235:genetics / Q000378:metabolism; D017361:Viral Nonstructural Proteins / Q000235:genetics / Q000378:metabolism; D014779:Virus Replication / Q000502:physiology*; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D000975:Antioxidants; D051267:NF-E2-Related Factor 2; D051257:Proto-Oncogene Proteins c-maf; D014758:Viral Core Proteins; D017361:Viral Nonstructural Proteins; C495607:MAF protein, human; C495635:NFE2L2 protein, human; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases