Li Zhubing, Liu Qiang
VIDO-InterVac, Vaccinology and Immunotherapeutics, University of Saskatchewan, Saskatoon, Saskatchewan, Canada.
VIDO-InterVac, Vaccinology and Immunotherapeutics, Veterinary Microbiology, University of Saskatchewan, Saskatoon, Saskatchewan, Canada.
Biochem Biophys Res Commun. 2018 Feb 19;496(4):1229-1235. doi: 10.1016/j.bbrc.2018.01.176. Epub 2018 Jan 31.
Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a secretory serine protease mainly expressed in liver. Although PCSK9 has been shown to inhibit hepatitis C virus (HCV) entry and replication, whether HCV regulates PCSK9 transcription has not been well studied. PCSK9 promoter activity is modulated by numerous transcription factors including sterol-regulatory element binding protein (SREBP)-1a, -1c, -2, hepatocyte nuclear factor-1 (HNF-1), and forkhead box O3 (FoxO3). Since they are differently regulated by HCV, we studied the effects of these transcription factors on PCSK9 promoter activity in the context of HCV infection and replication. We demonstrated that PCSK9 promoter activity was up-regulated after HCV infection and in HCV genomic replicon cells. We also studied the effects of HCV proteins on the PCSK9 promoter activity. While HCV structural proteins core, E1, and E2 had no effect, NS2, NS3, NS3-4A, NS5A and NS5B enhanced, and p7 and NS4B decreased PCSK9 promoter activity. Furthermore, we showed that transcription factors SREBP-1c, HNF-1α and specificity protein 1 increased PCSK9 promoter activity in HCV replicon cells, whereas SREBP-1a, HNF-1β and FoxO3 had an inhibitory effect. These results demonstrated the molecular mechanisms of how HCV modulates PCSK9 promoter activity and advanced our understanding on the mutual interactions between HCV and PCSK9.
前蛋白转化酶枯草杆菌蛋白酶/kexin 9型（PCSK9）是一种主要在肝脏中表达的分泌性丝氨酸蛋白酶。尽管已表明PCSK9可抑制丙型肝炎病毒（HCV）的进入和复制，但HCV是否调节PCSK9转录尚未得到充分研究。PCSK9启动子活性受多种转录因子调节，包括固醇调节元件结合蛋白（SREBP）-1a、-1c、-2、肝细胞核因子-1（HNF-1）和叉头框O3（FoxO3）。由于它们受HCV的调节方式不同，我们研究了这些转录因子在HCV感染和复制情况下对PCSK9启动子活性的影响。我们证明，HCV感染后以及在HCV基因组复制子细胞中，PCSK9启动子活性上调。我们还研究了HCV蛋白对PCSK9启动子活性的影响。虽然HCV结构蛋白核心、E1和E2没有影响，但NS2、NS3、NS3-4A、NS5A和NS5B增强了PCSK9启动子活性，而p7和NS4B则降低了其活性。此外，我们表明转录因子SREBP-1c、HNF-1α和特异性蛋白1在HCV复制子细胞中增加了PCSK9启动子活性，而SREBP-1a、HNF-1β和FoxO3具有抑制作用。这些结果证明了HCV调节PCSK9启动子活性的分子机制，并加深了我们对HCV与PCSK9之间相互作用的理解。
