Molecular Virology Laboratory, Hellenic Pasteur Institute, V. Sofias ave., 11521 Athens, Greece.
Fundación Banco Bilbao Vizcaya (F-BBVA) - CNIO Cancer Cell Biology Program, Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain.
J Gen Virol. 2013 Jul;94(Pt 7):1528-1534. doi: 10.1099/vir.0.050328-0. Epub 2013 Apr 11.
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.
慢性丙型病毒性肝炎的特征是肝脏中铁质蓄积，而铁调素调节铁吸收。丙型肝炎病毒（HCV）核心+1/ARFP 是一种在核心基因内的第二个功能性 ORF 产生的新型蛋白。在这里，我们使用报告基因检测和 HCV 双顺反子复制子，表明与核心蛋白相似，核心+1/ARFP 降低肝癌细胞中铁调素的表达。我们在这里显示人铁调素启动子的激活蛋白 1（AP1）结合位点与基础启动子活性和核心蛋白的抑制作用相关，对于核心+1/ARFP 的下调是必需的，而之前描述的 C/EBP（CCAAT/增强子结合蛋白）和 STAT（信号转导和转录激活因子）位点则不是。一致地，AP1 成分 c-jun 和 c-fos 的表达消除了核心和核心+1/ARFP 的抑制作用。总之，我们提供了证据表明核心+1/ARFP 下调了 AP1 介导的转录，为核心+1/ARFP 的生物学作用以及铁代谢的主要调节剂铁调素的转录调节提供了新的见解。
