Prenylation in antiviral immunity

摘要 在这项提案中，我们将探讨预烯基化在抗病毒免疫中的作用。预基化是一种翻译后的 使蛋白质疏水，从而将其靶向于内膜的修饰。虽然这一角色 免疫中的预烯基化作用尚不清楚，我们的初步数据显示，令人信服的证据表明，预烯基化是一种 修饰广泛应用于先天抗病毒免疫。因为宿主和病毒都利用戊烯基化和 胆固醇的生物合成途径，我们提出了一个动态的宿主-病原体在这个界面上的相互作用。我们 假设戊烯基化可能是对抗病毒致病的一种有效的宿主创新。这是基于 在硅胶分析中，发现免疫相关蛋白富含预烯基化基序。我们 随后进行了硅胶分析和生化筛选，并鉴定了几种预烯基化的抗病毒蛋白 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。在这项研究中，我们建议确定前烯基化蛋白对亚细胞的功能影响。 定位、干扰素信号和抗病毒功能。通过在戊烯基化反应中干扰特定的酶 我们将研究其对干扰素反应、抗病毒效应物和病毒控制的影响。这项工作将 为细胞内源性抗病毒对策和新型抗病毒药物的开发提供新的见解 目标。

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.