Dissecting the mechanism of signaling-triggered nuclear export of newly synthesized influenza virus ribonucleoprotein complexes

Proc Natl Acad Sci U S A. 2020 Jul 14;117(28):16557-16566. doi: 10.1073/pnas.2002828117. Epub 2020 Jun 29.


Influenza viruses (IV) exploit a variety of signaling pathways. Previous studies showed that the rapidly accelerated fibrosarcoma/mitogen-activated protein kinase/extracellular signal-regulated kinase (Raf/MEK/ERK) pathway is functionally linked to nuclear export of viral ribonucleoprotein (vRNP) complexes, suggesting that vRNP export is a signaling-induced event. However, the underlying mechanism remained completely enigmatic. Here we have dissected the unknown molecular steps of signaling-driven vRNP export. We identified kinases RSK1/2 as downstream targets of virus-activated ERK signaling. While RSK2 displays an antiviral role, we demonstrate a virus-supportive function of RSK1, migrating to the nucleus to phosphorylate nucleoprotein (NP), the major constituent of vRNPs. This drives association with viral matrix protein 1 (M1) at the chromatin, important for vRNP export. Inhibition or knockdown of MEK, ERK or RSK1 caused impaired vRNP export and reduced progeny virus titers. This work not only expedites the development of anti-influenza strategies, but in addition demonstrates converse actions of different RSK isoforms.

Keywords: RSK; Raf/MEK/ERK pathway; influenza virus.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Active Transport, Cell Nucleus
  • Cell Nucleus / metabolism
  • Cell Nucleus / virology
  • Humans
  • Influenza A virus / genetics
  • Influenza A virus / metabolism*
  • Influenza, Human / genetics
  • Influenza, Human / metabolism
  • Influenza, Human / virology*
  • MAP Kinase Signaling System
  • Nuclear Export Signals
  • Ribonucleoproteins / genetics
  • Ribonucleoproteins / metabolism*
  • Ribosomal Protein S6 Kinases, 90-kDa / genetics
  • Ribosomal Protein S6 Kinases, 90-kDa / metabolism
  • Viral Matrix Proteins / genetics
  • Viral Matrix Proteins / metabolism


  • Nuclear Export Signals
  • Ribonucleoproteins
  • Viral Matrix Proteins
  • RPS6KA1 protein, human
  • Ribosomal Protein S6 Kinases, 90-kDa
  • ribosomal protein S6 kinase, 90kDa, polypeptide 3