title: Hepatitis C virus core+1/ARF protein decreases hepcidin transcription through an AP1 binding site.
abstract: Chronic viral hepatitis C is characterized by iron accumulation in the liver, and hepcidin regulates iron absorption. Hepatitis C virus (HCV) core+1/ARFP is a novel protein produced by a second functional ORF within the core gene. Here, using reporter assays and HCV bicistronic replicons, we show that, similarly to core, core+1/ARFP decreases hepcidin expression in hepatoma cells. The activator protein 1 (AP1) binding site of the human hepcidin promoter, shown here to be relevant to basal promoter activity and to the repression by core, is essential for the downregulation by core+1/ARFP while the previously described C/EBP (CCAAT/enhancer binding protein) and STAT (signal transducer and activator of transcription) sites are not. Consistently, expression of the AP1 components c-jun and c-fos obliterated the repressive effect of core and core+1/ARFP. In conclusion, we provide evidence that core+1/ARFP downregulates AP1-mediated transcription, providing new insights into the biological role of core+1/ARFP, as well as the transcriptional modulation of hepcidin, the main regulator of iron metabolism.
authors.affiliation: Molecular Virology Laboratory, Hellenic Pasteur Institute, V. Sofias ave., 11521 Athens, Greece.
authors.forename: Ioly
authors.initials: I
authors.lastname: Kotta-Loizou
authors.affiliation: Molecular Virology Laboratory, Hellenic Pasteur Institute, V. Sofias ave., 11521 Athens, Greece.
authors.forename: Niki
authors.initials: N
authors.lastname: Vassilaki
authors.affiliation: Molecular Virology Laboratory, Hellenic Pasteur Institute, V. Sofias ave., 11521 Athens, Greece.
authors.forename: George
authors.initials: G
authors.lastname: Pissas
authors.affiliation: Molecular Virology Laboratory, Hellenic Pasteur Institute, V. Sofias ave., 11521 Athens, Greece.
authors.forename: Athanassios
authors.initials: A
authors.lastname: Kakkanas
authors.affiliation: Fundación Banco Bilbao Vizcaya (F-BBVA) - CNIO Cancer Cell Biology Program, Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain.
authors.forename: Latifa
authors.initials: L
authors.lastname: Bakiri
authors.affiliation: Department of Infectious Diseases, Molecular Virology, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Ralf
authors.initials: R
authors.lastname: Bartenschlager
authors.affiliation: Molecular Virology Laboratory, Hellenic Pasteur Institute, V. Sofias ave., 11521 Athens, Greece.
authors.forename: Penelope
authors.initials: P
authors.lastname: Mavromara
mesh_terms: D000900:Anti-Bacterial Agents / Q000378:metabolism; D023181:Antimicrobial Cationic Peptides / Q000378:metabolism*; D001665:Binding Sites; D045744:Cell Line, Tumor; D015536:Down-Regulation; D016174:Hepacivirus / Q000472:pathogenicity*; D064451:Hepcidins; D006801:Humans; D007501:Iron / Q000378:metabolism; D008099:Liver / Q000166:cytology; D011401:Promoter Regions, Genetic; D018808:Transcription Factor AP-1 / Q000737:chemistry* / Q000378:metabolism; D015533:Transcriptional Activation; D014758:Viral Core Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D000900:Anti-Bacterial Agents; D023181:Antimicrobial Cationic Peptides; C578702:HAMP protein, human; D064451:Hepcidins; D018808:Transcription Factor AP-1; D014758:Viral Core Proteins; C433031:hepatitis C protein F, Hepatitis C virus; D007501:Iron