Prenylation in antiviral immunity

抗病毒免疫中的异戊二烯化

• 批准号: 10647533
• 负责人: Ram Savan
• 金额: $ 64.66万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-14 至 2028-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10647533
• 关键词: Antiviral Response; Genes; Interferons; Location; NFIB gene; Play; Virus Diseases; antiviral immunity; insight; novel; prenylation

Summary In this proposal, we will explore the role of prenylation in antiviral immunity. Prenylation is a post-translational modification that renders proteins hydrophobic, thus targeting them to the endomembrane. While the role of prenylation in immunity is unclear, our preliminary data shows compelling evidence that prenylation is a modification widely used in innate antiviral immunity. As both the host and virus utilize prenylation and the cholesterol biosynthetic pathway, we propose a dynamic host-pathogen interaction at this interface. We hypothesize that prenylation could be a potent host innovation to counter viral pathogenesis. This is based on in silica analysis that revealed an enrichment of immunity-related proteins with a prenylation motif. We followed in-silica analyses with a biochemical screen and identified several prenylated antiviral proteins that are involved in interferon responses and virus restriction, with potential to affect virus entry, replication, and egress. In this grant, we propose to identify the functional consequences of prenylated proteins on subcellular localization, interferon signaling, and antiviral function. By perturbing specific enzymes in the prenylation pathway, we will study its effect on interferon response, antiviral effectors, and virus control. This work will provide novel insights into cell-intrinsic antiviral countermeasures and the development of novel antiviral drug targets.

概括 在此提案中，我们将探讨原始化在抗病毒免疫中的作用。培养基是一种翻译 使蛋白质疏水，从而将其靶向内膜的修饰。而角色 免疫力中的前化尚不清楚，我们的初步数据表明，令人信服的证据表明前烯基化是一种 修饰广泛用于先天抗病毒免疫。由于宿主和病毒都利用前苯和 胆固醇生物合成途径，我们在该界面提出了动态的宿主 - 病原体相互作用。我们 假设前化可能是对抗病毒发病机理的有效宿主创新。这是基于 在二氧化硅分析中，该分析揭示了与先前化基序的免疫相关蛋白的富集。我们 跟随二氧化硅对生化筛查进行分析，并鉴定出几种原始的抗病毒药蛋白，这些蛋白 参与干扰素反应和病毒限制，有可能影响病毒进入，复制和 出口。在这笔赠款中，我们建议识别蛋白质对亚细胞的功能后果 定位，干扰素信号传导和抗病毒功能。通过扰动特定酶在原始化中 途径，我们将研究其对干扰素反应，抗病毒效应子和病毒控制的影响。这项工作将 提供有关细胞中性抗病毒对策和新型抗病毒药物的新见解 目标。