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

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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.