Phosphoproteomic-based kinase profiling early in influenza virus infection identifies GRK2 as antiviral drug target

Emilio Yángüez, Annika Hunziker, Maria Pamela Dobay, Soner Yildiz, Simon Schading, Elizaveta Elshina, Umut Karakus, Peter Gehrig, Jonas Grossmann, Ronald Dijkman, Mirco Schmolke and Silke Stertz ()
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Emilio Yángüez: Institute of Medical Virology
Annika Hunziker: Institute of Medical Virology
Maria Pamela Dobay: SIB Swiss Institute of Bioinformatics
Soner Yildiz: University of Geneva
Simon Schading: Institute of Medical Virology
Elizaveta Elshina: Institute of Medical Virology
Umut Karakus: Institute of Medical Virology
Peter Gehrig: Functional Genomics Centre Zurich
Jonas Grossmann: Functional Genomics Centre Zurich
Ronald Dijkman: Institute of Virology and Immunology
Mirco Schmolke: University of Geneva
Silke Stertz: Institute of Medical Virology

Nature Communications, 2018, vol. 9, issue 1, 1-13

Abstract: Abstract Although annual influenza epidemics affect around 10% of the global population, current treatment options are limited and development of new antivirals is needed. Here, using quantitative phosphoproteomics, we reveal the unique phosphoproteome dynamics that occur in the host cell within minutes of influenza A virus (IAV) infection. We uncover cellular kinases required for the observed signaling pattern and find that inhibition of selected candidates, such as the G protein-coupled receptor kinase 2 (GRK2), leads to decreased IAV replication. As GRK2 has emerged as drug target in heart disease, we focus on its role in IAV infection and show that it is required for viral uncoating. Replication of seasonal and pandemic IAVs is severely decreased by specific GRK2 inhibitors in primary human airway cultures and in mice. Our study reveals the IAV-induced changes to the cellular phosphoproteome and identifies GRK2 as crucial node of the kinase network that enables IAV replication.

Date: 2018
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DOI: 10.1038/s41467-018-06119-y

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