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

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


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Antiviral Agents / pharmacology*
  • Cells, Cultured
  • Enzyme Activation / drug effects
  • G-Protein-Coupled Receptor Kinase 2 / antagonists & inhibitors*
  • G-Protein-Coupled Receptor Kinase 2 / metabolism
  • Humans
  • Influenza, Human / metabolism*
  • Influenza, Human / virology*
  • Lung / pathology
  • Lung / virology
  • Mice
  • Molecular Targeted Therapy*
  • Orthomyxoviridae Infections / metabolism
  • Orthomyxoviridae Infections / virology
  • Phosphoproteins / chemistry
  • Phosphoproteins / metabolism*
  • Phosphorylation / drug effects
  • Protein Kinases / metabolism*
  • Proteomics / methods*
  • Virus Internalization / drug effects
  • Virus Replication / drug effects


  • Antiviral Agents
  • Phosphoproteins
  • Protein Kinases
  • GRK2 protein, human
  • G-Protein-Coupled Receptor Kinase 2