RAPID: Determination of SARS-CoV-2 Spike Glycoprotein Palmitoylation and its Contribution to Virus-Cell Fusion and Surface Protein-Protein Interactions

冠状病毒，如COVID-19的病原体SARS-CoV-2，是一种包膜RNA病毒，编码三种包膜蛋白——刺突糖蛋白(S)、包膜蛋白(E)和膜蛋白(M)。特别令人感兴趣的是冠状病毒S蛋白，它覆盖在病毒表面，形成独特的“冠状”结构。S蛋白负责与宿主细胞表面的特定受体相互作用，从而启动病毒进入和感染。本项目研究S蛋白棕榈酰化（S蛋白的一种化学修饰，加入一种脂肪酸）在病毒与宿主细胞融合和病毒感染性中的作用。了解S蛋白棕榈酰化在病毒传染性中的作用，有助于开发新的治疗靶点，阻断COVID-19的传染性。该项目还将有助于两名研究生的跨学科培训。此外，PI将通过与圣地亚哥科学项目（一个K-12专业发展和教师支持组织）的合作，与圣地亚哥教育界和公众开展外展活动。这项RAPID提案的目标是探索棕榈酰化如何通过s介导的膜融合和宿主细胞受体相互作用介导病毒进入和感染SARS-CoV-2。pi提出，SARS-CoV-2刺突糖蛋白的棕榈酰化对于导致宿主感染的这些重要病毒过程是必要的。该项目的具体目的是：(1)确定SARS-CoV-2刺突糖蛋白中棕榈酰化的半胱氨酸残基。(2)表征S蛋白定位的棕榈酰化依赖性以及S介导的病毒-细胞融合。(3)评估宿主细胞表面受体与新型冠状病毒S蛋白之间蛋白相互作用的棕榈酰化依赖性变化。了解S蛋白棕榈酰化的功能结果有助于更好地了解棕榈酰化在细胞动力学和功能中的作用，并可能促进新冠肺炎治疗方法的开发。该RAPID奖由分子和细胞生物科学部的细胞动力学和功能项目获得，资金来自《冠状病毒援助、救济和经济安全法案》。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

Coronaviruses, such as SARS-CoV-2, the causative agent of COVID-19, are enveloped RNA viruses that encode three envelope proteins – spike glycoprotein (S), envelope protein (E), and membrane protein (M). Of special interest are the coronavirus S proteins, which coat the surface of the virus and form the distinctive “corona” structure. S proteins are responsible for interacting with specific receptors on the surface of host cells, thus initiating virus entry and infection. This project examines the role of S protein palmitoylation, a chemical modification of the S protein with the addition of a fatty acid, in the fusion of the virus to the host cell, and virus infectivity. Understanding the role of S protein palmitoylation in virus infectivity can lead to the development of new therapeutic targets that block the infectivity of COVID-19. This project will also contribute to the interdisciplinary training of two graduate students. In addition, PI will engage in outreach activities with the San Diego educational community and the public, in part through a collaboration with the San Diego Science project, a K-12 professional development and teacher support organization.The goal of this RAPID proposal is to explore how palmitoylation mediates viral entry and infection of SARS-CoV-2, through S-mediated membrane fusion and host cell receptor interactions. The PIs propose that palmitoylation of the SARS-CoV-2 spike glycoprotein is necessary for these important viral processes that lead to host infection. The specific aims of this project are: (1) Determining the cysteine residues that are palmitoylated in the SARS-CoV-2 spike glycoprotein. (2) Characterizing the palmitoylation-dependence of S protein localization as well as S-mediated virus-cell fusion. (3) Evaluating the palmitoylation-dependent change in protein-protein interactions between host cell surface receptors and the novel coronavirus S protein. Understanding the functional outcomes of S protein palmitoylation can help better understand the role of palmitoylation in cellular dynamics and function and possibly spur development of novel therapeutics for the treatment of COVID-19.This RAPID award is made by the Cellular Dynamics and Function Program in the Division of Molecular and Cellular Biosciences, using funds from the Coronavirus Aid, Relief, and Economic Security (CARES) Act.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.