2. Academic Validation
  3. The Global Phosphorylation Landscape of SARS-CoV-2 Infection

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.
Mehdi Bouhaddou 1,  Danish Memon 2,  Bjoern Meyer 3,  Kris M White 4,  Veronica V Rezelj 3,  Miguel Correa Marrero 2,  Benjamin J Polacco 1,  James E Melnyk 5,  Svenja Ulferts 6,  Robyn M Kaake 1,  Jyoti Batra 1,  Alicia L Richards 1,  Erica Stevenson 1,  David E Gordon 1,  Ajda Rojc 1,  Kirsten Obernier 1,  Jacqueline M Fabius 1,  Margaret Soucheray 1,  Lisa Miorin 4,  Elena Moreno 4,  Cassandra Koh 3,  Quang Dinh Tran 3,  Alexandra Hardy 3,  Rémy Robinot 7,  Thomas Vallet 3,  Benjamin E Nilsson-Payant 8,  Claudia Hernandez-Armenta 2,  Alistair Dunham 2,  Sebastian Weigang 9,  Julian Knerr 6,  Maya Modak 1,  Diego Quintero 1,  Yuan Zhou 1,  Aurelien Dugourd 10,  Alberto Valdeolivas 10,  Trupti Patil 1,  Qiongyu Li 1,  Ruth Hüttenhain 1,  Merve Cakir 1,  Monita Muralidharan 1,  Minkyu Kim 1,  Gwendolyn Jang 1,  Beril Tutuncuoglu 1,  Joseph Hiatt 1,  Jeffrey Z Guo 1,  Jiewei Xu 1,  Sophia Bouhaddou 11,  Christopher J P Mathy 12,  Anna Gaulton 2,  Emma J Manners 2,  Eloy Félix 2,  Ying Shi 5,  Marisa Goff 8,  Jean K Lim 8,  Timothy McBride 13,  Michael C O'Neal 13,  Yiming Cai 13,  Jason C J Chang 13,  David J Broadhurst 13,  Saker Klippsten 13,  Emmie De Wit 14,  Andrew R Leach 2,  Tanja Kortemme 12,  Brian Shoichet 15,  Melanie Ott 16,  Julio Saez-Rodriguez 10,  Benjamin R tenOever 8,  R Dyche Mullins 5,  Elizabeth R Fischer 14,  Georg Kochs 17,  Robert Grosse 18,  Adolfo García-Sastre 19,  Marco Vignuzzi 20,  Jeffery R Johnson 21,  Kevan M Shokat 22,  Danielle L Swaney 23,  Pedro Beltrao 24,  Nevan J Krogan 25
Affiliations

Affiliations

  • 1 QBI COVID-19 Research Group (QCRG), San Francisco, CA 94158, USA; Quantitative Biosciences Institute (QBI), University of California, San Francisco, San Francisco, CA 94158, USA; J. David Gladstone Institutes, San Francisco, CA 94158, USA; Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA.
  • 2 European Molecular Biology Laboratory (EMBL), European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, Cambridge, UK.
  • 3 Viral Populations and Pathogenesis Unit, CNRS UMR 3569, Institut Pasteur, 75724 Paris, Cedex 15, France.
  • 4 Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
  • 5 QBI COVID-19 Research Group (QCRG), San Francisco, CA 94158, USA; Quantitative Biosciences Institute (QBI), University of California, San Francisco, San Francisco, CA 94158, USA; Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA; Howard Hughes Medical Institute.
  • 6 Institute for Clinical and Experimental Pharmacology and Toxicology, University of Freiburg, Freiburg 79104, Germany.
  • 7 Virus & Immunity Unit, Department of Virology, CNRS UMR 3569, Institut Pasteur, 75724 Paris, Cedex 15, France; Vaccine Research Institute, 94000 Creteil, France.
  • 8 Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
  • 9 Institute of Virology, Medical Center - University of Freiburg, Freiburg 79104, Germany.
  • 10 Institute for Computational Biomedicine, Bioquant, Heidelberg University, Faculty of Medicine, and Heidelberg University Hospital, Heidelberg 69120, Germany.
  • 11 QBI COVID-19 Research Group (QCRG), San Francisco, CA 94158, USA.
  • 12 QBI COVID-19 Research Group (QCRG), San Francisco, CA 94158, USA; Quantitative Biosciences Institute (QBI), University of California, San Francisco, San Francisco, CA 94158, USA; Department of Bioengineering & Therapeutic Sciences, University of California, San Francisco, San Francisco, CA 94158, USA.
  • 13 Zoic Labs, Culver City, CA 90232, USA.
  • 14 NIH/NIAID/Rocky Mountain Laboratories, Hamilton, MT 59840, USA.
  • 15 QBI COVID-19 Research Group (QCRG), San Francisco, CA 94158, USA; Quantitative Biosciences Institute (QBI), University of California, San Francisco, San Francisco, CA 94158, USA.
  • 16 J. David Gladstone Institutes, San Francisco, CA 94158, USA.
  • 17 Institute of Virology, Medical Center - University of Freiburg, Freiburg 79104, Germany; Faculty of Medicine, University of Freiburg, Freiburg 79008, Germany.
  • 18 Institute for Clinical and Experimental Pharmacology and Toxicology, University of Freiburg, Freiburg 79104, Germany; Faculty of Medicine, University of Freiburg, Freiburg 79008, Germany; Centre for Integrative Biological Signalling Studies (CIBSS), Freiburg 79104, Germany. Electronic address: robert.grosse@pharmakol.uni-freiburg.de.
  • 19 Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA; The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA. Electronic address: adolfo.garcia-sastre@mssm.edu.
  • 20 Viral Populations and Pathogenesis Unit, CNRS UMR 3569, Institut Pasteur, 75724 Paris, Cedex 15, France. Electronic address: marco.vignuzzi@pasteur.fr.
  • 21 Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Electronic address: jeffrey.johnson@mssm.edu.
  • 22 QBI COVID-19 Research Group (QCRG), San Francisco, CA 94158, USA; Quantitative Biosciences Institute (QBI), University of California, San Francisco, San Francisco, CA 94158, USA; Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA; Howard Hughes Medical Institute. Electronic address: kevan.shokat@ucsf.edu.
  • 23 QBI COVID-19 Research Group (QCRG), San Francisco, CA 94158, USA; Quantitative Biosciences Institute (QBI), University of California, San Francisco, San Francisco, CA 94158, USA; J. David Gladstone Institutes, San Francisco, CA 94158, USA; Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA. Electronic address: danielle.swaney@ucsf.edu.
  • 24 QBI COVID-19 Research Group (QCRG), San Francisco, CA 94158, USA; European Molecular Biology Laboratory (EMBL), European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, Cambridge, UK. Electronic address: pbeltrao@ebi.ac.uk.
  • 25 QBI COVID-19 Research Group (QCRG), San Francisco, CA 94158, USA; Quantitative Biosciences Institute (QBI), University of California, San Francisco, San Francisco, CA 94158, USA; J. David Gladstone Institutes, San Francisco, CA 94158, USA; Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA; Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Electronic address: nevan.krogan@ucsf.edu.
PMID: 32645325 DOI: 10.1016/j.cell.2020.06.034
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.

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