柯萨奇病毒B3非结构蛋白3C调控SREBP1促进病毒复制的分子机制研究

项目名称： 柯萨奇病毒B3非结构蛋白3C调控SREBP1促进病毒复制的分子机制研究

项目编号： No.81501738

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 谢玮

作者单位： 中国人民解放军第三军医大学

项目金额： 18万元

中文摘要： 柯萨奇病毒B3是引起病毒性心肌炎最为常见的病原体。我们在前期工作中发现CVB3感染通过增加脂质合成引起细胞内脂质积累，促进病毒复制，但是CVB3调控脂质合成的机制并不清楚。SREBP1是调控脂质合成的关键转录因子，在前期研究中我们发现CVB3非结构蛋白3C可以上调SREBP1的转录，因此推测CVB3感染细胞后通过表达3C上调SREBP1的转录及活性，提高脂质合成酶基因表达，进而促进脂质积累和病毒复制。本项目拟构建SREBP1及其下游基因的启动子报告基因，研究3C调控SREBP1转录及活性的分子机制，确定参与3C调控SREBP1的转录因子，探讨Akt及AMPK通路在其中的作用；并利用RNA干扰明确SREBP1在CVB3调控脂质合成中的作用，阐明CVB3增加宿主细胞脂质合成积累的分子机制。研究结果将为了解CVB3病毒与宿主的相互作用提供新的认识，也将为治疗CVB3感染引发的心肌炎提供新的思路。

中文关键词： 肠道病毒；柯萨奇病毒B3；非结构蛋白3C；SREBP1；转录调控

英文摘要： Coxsackievirus B3 (CVB3) is the major pathogen of human viral myocarditis. In our previous work, it has been found that CVB3 infection increased the cellular lipid synthesis and accumulation which was beneficial to virus replication. However, the regulation mechanisms of lipid synthesis during CVB3 infection are not well understood. We further found that CVB3 nonstructural protein 3C was found to increase the transcription of sterol regulatory element-binding protein-1 (SREBP1), which is the key transcriptional factor in regulating lipogenic gene expression. The SREBP1 transcriptionally activates a cascade of enzymes required for endogenous lipid synthesis, including fatty acid synthase (Fasn) and acetyl-CoA carboxylase (ACC). These results suggest that CVB3 nonstructural protein 3C activates SREBP1 and its downstream lipogenic genes expression to increase the cellular lipid accumulation and virus replication. In this study, the regulation mechanisms of SREBP1 transcription and activity by CVB3 3C will be investigated. The potential transcriptional factors contributing to the regulation of SREBP1 by 3C will be determined. Furthermore, the effects of PI3K/Akt and AMPK signaling in modulation of SREBP1 transcription and activity during CVB3 infection or 3C expression will be explored. At last, the effects of SREBP1 in CVB3 induced lipogenesis and virus replication will also be evaluated by the RNA interference of SREBP1. This study will elucidate the molecular mechanisms of increase in lipid synthesis and accumulation during CVB3 infection, and will probably benefit the research of treatment of CVB3-induced myocarditis.

英文关键词： Enterovirus;Coxsackievirus B3;nonstructural protein 3C;SREBP1;transcriptional regulation