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

RAPID：测定 SARS-CoV-2 刺突糖蛋白棕榈酰化及其对病毒-细胞融合和表面蛋白-蛋白质相互作用的贡献

• 批准号: 2031068
• 负责人: Neal Devaraj
• 金额: $ 20万
• 依托单位: University of California-San Diego
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-15 至 2022-05-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2031068&HistoricalAwards=false
• 关键词: RAPID; Determination; SARS; CoV; Spike

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.

冠状病毒，如新冠肺炎的病原体SARS-CoV-2，是一种囊膜核糖体病毒，编码3种囊膜蛋白--刺状糖蛋白(S)、囊膜蛋白(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，从而启动病毒的进入和感染。这个项目研究了S蛋白的棕榈酰化，即S蛋白的一种添加了脂肪酸的化学修饰，在病毒与宿主细胞的融合中的作用，以及病毒的感染性。了解S蛋白棕榈酰化在病毒感染性中的作用，可以导致开发新的治疗靶点来阻断新冠肺炎的感染性。该项目还将有助于对两名研究生进行跨学科培训。此外，PI将与圣地亚哥教育界和公众进行外联活动，部分是通过与圣地亚哥科学项目的合作，圣地亚哥科学项目是一个K-12专业发展和教师支持组织。这个快速提案的目标是探索棕榈酰化如何通过S介导膜融合和宿主细胞受体相互作用介导SARS-CoV-2的病毒入侵和感染。PI认为SARS-CoV-2刺突糖蛋白的棕榈酰化对于这些导致宿主感染的重要病毒过程是必要的。本项目的具体目标是：(1)测定SARS-CoV-2刺突糖蛋白中棕榈酰化的半胱氨酸残基。(2)S蛋白定位的棕榈酰化依赖性特征以及S介导的病毒-细胞融合。(3)评价新型冠状病毒S蛋白与宿主细胞表面受体之间蛋白-蛋白相互作用的棕榈酰化依赖变化。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，并可能促进治疗COVID-19的新疗法的开发。这一快速奖项由分子和细胞生物科学部门的细胞动力学和功能计划颁发，资金来自冠状病毒援助、救济和经济安全(CARE)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智力优势和更广泛的影响审查标准进行评估，被认为值得支持。