The Global Phosphorylation Landscape of SARS-CoV-2 Infection

Cell. 2020 Aug 6;182(3):685-712.e19. doi: 10.1016/j.cell.2020.06.034. Epub 2020 Jun 28.

Abstract

The causative agent of the coronavirus disease 2019 (COVID-19) pandemic, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has infected millions and killed hundreds of thousands of people worldwide, highlighting an urgent need to develop antiviral therapies. Here we present a quantitative mass spectrometry-based phosphoproteomics survey of SARS-CoV-2 infection in Vero E6 cells, revealing dramatic rewiring of phosphorylation on host and viral proteins. SARS-CoV-2 infection promoted casein kinase II (CK2) and p38 MAPK activation, production of diverse cytokines, and shutdown of mitotic kinases, resulting in cell cycle arrest. Infection also stimulated a marked induction of CK2-containing filopodial protrusions possessing budding viral particles. Eighty-seven drugs and compounds were identified by mapping global phosphorylation profiles to dysregulated kinases and pathways. We found pharmacologic inhibition of the p38, CK2, CDK, AXL, and PIKFYVE kinases to possess antiviral efficacy, representing potential COVID-19 therapies.

Keywords: AXL; CDK; MAPK; PIKFYVE; SARS-CoV-2; antiviral; casein kinase II; mass spectrometry; p38; phosphoproteomics.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • A549 Cells
  • Angiotensin-Converting Enzyme 2
  • Animals
  • Antiviral Agents / pharmacology
  • Betacoronavirus / metabolism*
  • COVID-19
  • Caco-2 Cells
  • Casein Kinase II / antagonists & inhibitors
  • Casein Kinase II / metabolism
  • Chlorocebus aethiops
  • Coronavirus Infections / metabolism*
  • Coronavirus Infections / virology
  • Cyclin-Dependent Kinases / antagonists & inhibitors
  • Cyclin-Dependent Kinases / metabolism
  • Drug Evaluation, Preclinical / methods*
  • HEK293 Cells
  • Host-Pathogen Interactions
  • Humans
  • Pandemics
  • Peptidyl-Dipeptidase A / genetics
  • Peptidyl-Dipeptidase A / metabolism
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphoinositide-3 Kinase Inhibitors / pharmacology
  • Phosphorylation
  • Pneumonia, Viral / metabolism*
  • Pneumonia, Viral / virology
  • Protein Kinase Inhibitors / pharmacology
  • Proteomics / methods*
  • Proto-Oncogene Proteins / antagonists & inhibitors
  • Proto-Oncogene Proteins / metabolism
  • Receptor Protein-Tyrosine Kinases / antagonists & inhibitors
  • Receptor Protein-Tyrosine Kinases / metabolism
  • SARS-CoV-2
  • Spike Glycoprotein, Coronavirus / metabolism
  • Vero Cells
  • p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • p38 Mitogen-Activated Protein Kinases / metabolism

Substances

  • Antiviral Agents
  • Phosphoinositide-3 Kinase Inhibitors
  • Protein Kinase Inhibitors
  • Proto-Oncogene Proteins
  • Spike Glycoprotein, Coronavirus
  • spike protein, SARS-CoV-2
  • PIKFYVE protein, human
  • Receptor Protein-Tyrosine Kinases
  • axl receptor tyrosine kinase
  • Casein Kinase II
  • Cyclin-Dependent Kinases
  • p38 Mitogen-Activated Protein Kinases
  • Peptidyl-Dipeptidase A
  • ACE2 protein, human
  • Angiotensin-Converting Enzyme 2