Yaron, Tomer MHeaton, Brook ELevy, Tyler MJohnson, Jared LJordan, Tristan XCohen, Benjamin MKerelsky, AlexanderLin, Ting-YuLiberatore, Katarina MBulaon, Danielle KVan Nest, Samantha JKoundouros, NikosKastenhuber, Edward RMercadante, Marisa NShobana-Ganesh, KripaHe, LongSchwartz, Robert EChen, ShuibingWeinstein, HarelElemento, OlivierPiskounova, ElenaNilsson-Payant, Benjamin ELee, GinaTrimarco, Joseph DBurke, Kaitlyn NHamele, Cait EChaparian, Ryan RHarding, Alfred TTata, AleksandraZhu, XinyuTata, Purushothama RaoSmith, Clare MPossemato, Anthony PTkachev, Sasha LHornbeck, Peter VBeausoleil, Sean AAnand, Shankara KAguet, FrançoisGetz, GadDavidson, Andrew DHeesom, KateKavanagh-Williamson, MaiaMatthews, David AtenOever, Benjamin RCantley, Lewis CBlenis, JohnHeaton, Nicholas S2023-10-012023-10-012022-101945-08771937-9145https://hdl.handle.net/10161/29042Multiple coronaviruses have emerged independently in the past 20 years that cause lethal human diseases. Although vaccine development targeting these viruses has been accelerated substantially, there remain patients requiring treatment who cannot be vaccinated or who experience breakthrough infections. Understanding the common host factors necessary for the life cycles of coronaviruses may reveal conserved therapeutic targets. Here, we used the known substrate specificities of mammalian protein kinases to deconvolute the sequence of phosphorylation events mediated by three host protein kinase families (SRPK, GSK-3, and CK1) that coordinately phosphorylate a cluster of serine and threonine residues in the viral N protein, which is required for viral replication. We also showed that loss or inhibition of SRPK1/2, which we propose initiates the N protein phosphorylation cascade, compromised the viral replication cycle. Because these phosphorylation sites are highly conserved across coronaviruses, inhibitors of these protein kinases not only may have therapeutic potential against COVID-19 but also may be broadly useful against coronavirus-mediated diseases.AnimalsMammalsHumansNucleocapsidGlycogen Synthase Kinase 3ThreonineSerineNucleocapsid ProteinsVirus ReplicationPhosphorylationCOVID-19SARS-CoV-2Protein Serine-Threonine KinasesJournal article2023-10-01