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Nat Commun. 2018 Sep 11;9(1):3679. doi: 10.1038/s41467-018-06119-y.

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

Author information

1
Institute of Medical Virology, Winterthurerstrasse 190, 8057, Zurich, Switzerland.
2
Bioinformatics Core Facility, SIB Swiss Institute of Bioinformatics, Quartier Sorge-Batiment Genopode, Lausanne, 1015, Switzerland.
3
Department of Microbiology and Molecular Medicine, University of Geneva, Rue Michel-Servet 1, CH-1211, Geneva, Switzerland.
4
Functional Genomics Centre Zurich, Winterthurerstrasse 190, 8057, Zurich, Switzerland.
5
Institute of Virology and Immunology, Länggassstrasse 122, 3012, Bern, Switzerland.
6
Department of Infectious Diseases and Pathobiology, Vetsuisse Faculty, University of Bern, Bern, Switzerland.
7
Institute of Medical Virology, Winterthurerstrasse 190, 8057, Zurich, Switzerland. stertz.silke@virology.uzh.ch.

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.

PMID:
30206219
PMCID:
PMC6133941
DOI:
10.1038/s41467-018-06119-y
[Indexed for MEDLINE]
Free PMC Article

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