Host protein kinases required for SARS-CoV-2 nucleocapsid phosphorylation and viral replication

Tomer M. Yaron, Brook E. Heaton, Tyler M. Levy, Jared L. Johnson, Tristan X. Jordan, Benjamin M. Cohen, Alexander Kerelsky, Ting Yu Lin, Katarina M. Liberatore, Danielle K. Bulaon, Samantha J. Van Nest, Nikos Koundouros, Edward R. Kastenhuber, Marisa N. Mercadante, Kripa Shobana-Ganesh, Long He, Robert E. Schwartz, Shuibing Chen, Harel Weinstein, Olivier ElementoElena Piskounova, Benjamin E. Nilsson-Payant, Gina Lee, Joseph D. Trimarco, Kaitlyn N. Burke, Cait E. Hamele, Ryan R. Chaparian, Alfred T. Harding, Aleksandra Tata, Xinyu Zhu, Purushothama Rao Tata, Clare M. Smith, Anthony P. Possemato, Sasha L. Tkachev, Peter V. Hornbeck, Sean A. Beausoleil, Shankara K. Anand, François Aguet, Gad Getz, Andrew D. Davidson, Kate Heesom, Maia Kavanagh-Williamson, David A. Matthews, Benjamin R. TenOever, Lewis C. Cantley, John Blenis, Nicholas S. Heaton

Research output: Contribution to journalArticlepeer-review

19 Scopus citations

Abstract

Multiple 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.

Original languageEnglish
Article numbereabm0808
JournalScience Signaling
Volume15
Issue number757
DOIs
StatePublished - 25 Oct 2022
Externally publishedYes

Bibliographical note

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