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Published on: December 23, 2020
The Global Phosphorylation Landscape of SARS-CoV-2 Infection
Mehdi Bouhaddou1, Danish Memon2, Bjoern Meyer3
1QBI 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.
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.
Insights
This study reveals how SARS-CoV-2 infection alters host cell phosphorylation, activating specific kinases and causing cell cycle arrest. Targeting these kinases with drugs shows potential for developing new severe acute respiratory syndrome coronavirus 2 therapies.
Area of Science:
- Virology
- Cell Biology
- Biochemistry
Background:
- The COVID-19 pandemic, caused by SARS-CoV-2, necessitates the development of effective antiviral treatments.
- Understanding the molecular mechanisms of viral infection is crucial for identifying therapeutic targets.
Purpose of the Study:
- To investigate the global phosphorylation changes in host and viral proteins during SARS-CoV-2 infection.
- To identify potential drug targets and therapeutic compounds for COVID-19.
Main Methods:
- Quantitative mass spectrometry-based phosphoproteomics was employed to analyze SARS-CoV-2 infected Vero E6 cells.
- Global phosphorylation profiles were mapped to dysregulated kinases and pathways.
Main Results:
- SARS-CoV-2 infection significantly altered host and viral protein phosphorylation.
- Key findings include activation of casein kinase II (CK2) and p38 MAPK, cytokine production, and cell cycle arrest.
- CK2-rich filopodial protrusions with budding viral particles were observed.
Conclusions:
- Pharmacologic inhibition of specific kinases (p38, CK2, CDK, AXL, PIKFYVE) demonstrated antiviral efficacy against SARS-CoV-2.
- These findings highlight potential therapeutic strategies for COVID-19 by targeting host-directed kinases.
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