Liefhebber Jolanda M P, Hague Charlotte V, Zhang Qifeng, Wakelam Michael J O, McLauchlan John
From the Medical Research Council-University of Glasgow Centre for Virus Research, 8 Church Street, Glasgow G11 5JR, Scotland, United Kingdom and.
The Babraham Institute, Babraham Research Campus, Cambridge CB22 3AT, United Kingdom.
J Biol Chem. 2014 Aug 1;289(31):21276-88. doi: 10.1074/jbc.M114.582999. Epub 2014 Jun 10.
In hepatitis C virus infection, replication of the viral genome and virion assembly are linked to cellular metabolic processes. In particular, lipid droplets, which store principally triacylglycerides (TAGs) and cholesterol esters (CEs), have been implicated in production of infectious virus. Here, we examine the effect on productive infection of triacsin C and YIC-C8-434, which inhibit synthesis of TAGs and CEs by targeting long-chain acyl-CoA synthetase and acyl-CoA:cholesterol acyltransferase, respectively. Our results present high resolution data on the acylglycerol and cholesterol ester species that were affected by the compounds. Moreover, triacsin C, which blocks both triglyceride and cholesterol ester synthesis, cleared most of the lipid droplets in cells. By contrast, YIC-C8-434, which only abrogates production of cholesterol esters, induced an increase in size of droplets. Although both compounds slightly reduced viral RNA synthesis, they significantly impaired assembly of infectious virions in infected cells. In the case of triacsin C, reduced stability of the viral core protein, which forms the virion nucleocapsid and is targeted to the surface of lipid droplets, correlated with lower virion assembly. In addition, the virus particles that were released from cells had reduced specific infectivity. YIC-C8-434 did not alter the association of core with lipid droplets but appeared to decrease production of infectious virus particles, suggesting a block in virion assembly. Thus, the compounds have antiviral properties, indicating that targeting synthesis of lipids stored in lipid droplets might be an option for therapeutic intervention in treating chronic hepatitis C virus infection.
在丙型肝炎病毒感染中，病毒基因组的复制和病毒粒子组装与细胞代谢过程相关联。特别是，主要储存三酰甘油（TAGs）和胆固醇酯（CEs）的脂滴，已被证明与传染性病毒的产生有关。在此，我们研究了曲菌素C和YIC-C8-434对有效感染的影响，这两种化合物分别通过靶向长链酰基辅酶A合成酶和酰基辅酶A：胆固醇酰基转移酶来抑制TAGs和CEs的合成。我们的结果提供了受这些化合物影响的酰基甘油和胆固醇酯种类的高分辨率数据。此外，阻断甘油三酯和胆固醇酯合成的曲菌素C清除了细胞中的大部分脂滴。相比之下，仅消除胆固醇酯产生的YIC-C8-434导致脂滴尺寸增加。尽管这两种化合物都略微降低了病毒RNA的合成，但它们显著损害了感染细胞中传染性病毒粒子的组装。就曲菌素C而言，形成病毒粒子核衣壳并靶向脂滴表面的病毒核心蛋白稳定性降低，这与较低的病毒粒子组装相关。此外，从细胞中释放的病毒颗粒的特异性感染力降低。YIC-C8-434没有改变核心与脂滴的结合，但似乎减少了传染性病毒颗粒的产生，表明在病毒粒子组装过程中存在阻断。因此，这些化合物具有抗病毒特性，这表明靶向脂滴中储存的脂质合成可能是治疗慢性丙型肝炎病毒感染的一种治疗干预选择。
