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.
Original language | English |
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Pages (from-to) | 1528-1534 |
Number of pages | 7 |
Journal | Journal of General Virology |
Volume | 94 |
Issue number | Pt 7 |
DOIs | |
Publication status | Published - Jul 2013 |
Externally published | Yes |
Keywords
- Anti-Bacterial Agents/metabolism
- Antimicrobial Cationic Peptides/metabolism
- Binding Sites
- Cell Line, Tumor
- Down-Regulation
- Hepacivirus/pathogenicity
- Hepcidins
- Humans
- Iron/metabolism
- Liver/cytology
- Promoter Regions, Genetic
- Transcription Factor AP-1/chemistry
- Transcriptional Activation
- Viral Core Proteins/genetics