Hepatitis C virus RNA replication is regulated by host geranylgeranylation and fatty acids
Hepatitis C virus RNA replication is regulated by host geranylgeranylation and fatty acids
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DOI：
10.1073/pnas.0409834102
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发表时间：
2005-02-15
影响因子：
11.1
通讯作者：
Chisari, FV
中科院分区：
文献类型：
--
作者：
Kapadia, SB;Chisari, FV
丙型肝炎病毒（HCV）感染是慢性肝炎、肝硬化和肝细胞癌的主要原因。我们的实验室以前已经证明，高水平的HCV复制在黑猩猩急性感染与参与脂质代谢的多个基因的调制，以及调节胆固醇和脂肪酸的生物合成的药物调节的亚基因组HCV复制子在Huh-7细胞的复制。在这篇文章中，我们表明，Huh-7细胞窝藏复制，全长HCV RNA表达水平升高的ATIP柠檬酸裂解酶和乙酰辅酶A合成酶基因，这两者都参与胆固醇和脂肪酸的生物合成。此外，我们证实，胆固醇生物合成途径控制HCV RNA复制通过调节细胞水平的香叶基香叶基焦磷酸，我们证明了香叶基香叶基化的影响取决于细胞的脂肪酸含量，我们表明，脂肪酸可以刺激或抑制HCV复制，这取决于它们的饱和度。这些结果说明了一个复杂的细胞调控网络，控制HCV RNA复制，大概是通过调节细胞和/或病毒蛋白与细胞膜的运输和关联，这表明这些途径的药理学操作可能有治疗慢性HCV感染的效果。
Hepatitis C virus (HCV) infection is a major cause of chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma. Our laboratory has previously demonstrated that high-level HCV replication during acute infection of chimpanzees is associated with the modulation of multiple genes involved in lipid metabolism, and that drugs that regulate cholesterol and fatty acid biosynthesis regulate the replication of the subgenomic HCV replicon in Huh-7 cells. In this article, we demonstrate that Huh-7 cells harboring replicating, full-length HCV RNAs express elevated levels of ATIP citrate lyase and acetyl-CoA synthetase genes, both of which are involved in cholesterol and fatty acid biosynthesis. Further, we confirm that the cholesterol-biosynthetic pathway controls HCV RNA replication by regulating the cellular levels of geranylgeranyl pyrophosphate, we demonstrate that the impact of geranylgeranylation depends on the fatty acid content of the cell, and we show that fatty acids can either stimulate or inhibit HCV replication, depending on their degree of saturation. These results illustrate a complex cellular-regulatory network that controls HCV RNA replication, presumably by modulating the trafficking and association of cellular and/or viral proteins with cellular membranes, suggesting that pharmacologic manipulation of these pathways may have a therapeutic effect in chronic HCV infection.