Open AccessHepatitis C virus core+1/ARF protein decreases hepcidin transcription through an AP1 binding site
Author(s) -
Ioly KottaLoizou,
Niki Vassilaki,
Georgios Pissas,
Athanassios Kakkanas,
Latifa Bakiri,
Ralf Bartenschlager,
Penelope Mavromara
Publication year - 2013
Publication title -
journal of general virology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.55
H-Index - 167
eISSN - 1465-2099
pISSN - 0022-1317
DOI - 10.1099/vir.0.050328-0
Subject(s) - ap 1 transcription factor , hepcidin , biology , activator (genetics) , stat protein , transcription (linguistics) , enhancer , microbiology and biotechnology , promoter , transcription factor , hbx , virology , hepatitis c virus , gene expression , virus , gene , hepatitis b virus , stat3 , signal transduction , immunology , biochemistry , linguistics , philosophy , inflammation
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.