2. Academic Validation
  3. Host protein kinases required for SARS-CoV-2 nucleocapsid phosphorylation and viral replication

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

  • Sci Signal. 2022 Oct 25;15(757):eabm0808. doi: 10.1126/scisignal.abm0808.
Tomer M Yaron 1 2 3 4 5,  Brook E Heaton 6,  Tyler M Levy 7,  Jared L Johnson 1 2,  Tristan X Jordan 8,  Benjamin M Cohen 1 2,  Alexander Kerelsky 1 2 3,  Ting-Yu Lin 1 2 9,  Katarina M Liberatore 1 2,  Danielle K Bulaon 3,  Samantha J Van Nest 10,  Nikos Koundouros 1 11,  Edward R Kastenhuber 1 2,  Marisa N Mercadante 1 2,  Kripa Shobana-Ganesh 1 2 9,  Long He 1 2,  Robert E Schwartz 4 12,  Shuibing Chen 13,  Harel Weinstein 3 4,  Olivier Elemento 3 4,  Elena Piskounova 1 14,  Benjamin E Nilsson-Payant 8,  Gina Lee 15,  Joseph D Trimarco 6,  Kaitlyn N Burke 6,  Cait E Hamele 6,  Ryan R Chaparian 6,  Alfred T Harding 6,  Aleksandra Tata 16,  Xinyu Zhu 6,  Purushothama Rao Tata 16,  Clare M Smith 6,  Anthony P Possemato 7,  Sasha L Tkachev 7,  Peter V Hornbeck 7,  Sean A Beausoleil 7,  Shankara K Anand 17,  François Aguet 17,  Gad Getz 17 18 19,  Andrew D Davidson 20,  Kate Heesom 21,  Maia Kavanagh-Williamson 20,  David A Matthews 20,  Benjamin R tenOever 8,  Lewis C Cantley 1 2 22 23,  John Blenis 1 11 24,  Nicholas S Heaton 6 25 26
Affiliations

Affiliations

  • 1 Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10021, USA.
  • 2 Department of Medicine, Weill Cornell Medicine, New York, NY 10021, USA.
  • 3 Englander Institute for Precision Medicine, Institute for Computational Biomedicine, Weill Cornell Medicine, New York, NY 10021, USA.
  • 4 Department of Physiology and Biophysics, Weill Cornell Medicine, New York, NY 10065, USA.
  • 5 Tri-Institutional PhD Program in Computational Biology and Medicine, Weill Cornell Medicine/Memorial Sloan Kettering Cancer Center/Rockefeller University, New York, NY 10021, USA.
  • 6 Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, NC 27710, USA.
  • 7 Cell Signaling Technology, Danvers, MA 01923, USA.
  • 8 Grossman School of Medicine, New York University, New York, NY 10016, USA.
  • 9 Cell and Developmental Biology Program, Weill Cornell Graduate School of Medical Sciences, New York, NY 10065, USA.
  • 10 Department of Radiation Oncology, Weill Cornell Medicine, New York, NY 10065, USA.
  • 11 Department of Pharmacology, Weill Cornell Medicine, New York, NY 10065, USA.
  • 12 Division of Gastroenterology and Hepatology, Department of Medicine, Weill Cornell Medicine, New York, NY 10065, USA.
  • 13 Department of Surgery, Weill Cornell Medicine, New York, NY 10065, USA.
  • 14 Department of Dermatology, Weill Cornell Medicine, New York, NY 10065, USA.
  • 15 Department of Microbiology and Molecular Genetics, Chao Family Comprehensive Cancer Center, University of California, Irvine School of Medicine, Irvine, CA 92868, USA.
  • 16 Department of Cell Biology, Duke University School of Medicine, Durham, NC 27710, USA.
  • 17 Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • 18 Department of Pathology, Harvard Medical School, Boston, MA 02115, USA.
  • 19 Cancer Center and Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA.
  • 20 School of Cellular and Molecular Medicine, University of Bristol, Bristol BS8 1TD, UK.
  • 21 Proteomics Facility, University of Bristol, Bristol BS8 1TD, UK.
  • 22 Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
  • 23 Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
  • 24 Department of Biochemistry, Weill Cornell Medicine, New York, NY 10065, USA.
  • 25 Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC 27710, USA.
  • 26 Duke Cancer Institute, Duke University School of Medicine, Durham, NC 27710, USA.
PMID: 36282911 DOI: 10.1126/scisignal.abm0808
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.

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