Alternative interaction sites in the influenza A virus nucleoprotein mediate viral escape from the importin-α7 mediated nuclear import pathway

FEBS J. 2019 Sep;286(17):3374-3388. doi: 10.1111/febs.14868. Epub 2019 May 25.


Influenza A viruses are able to adapt to restrictive conditions due to their high mutation rates. Importin-α7 is a component of the nuclear import machinery required for avian-mammalian adaptation and replicative fitness in human cells. Here, we elucidate the mechanisms by which influenza A viruses may escape replicative restriction in the absence of importin-α7. To address this question, we assessed viral evolution in mice lacking the importin-α7 gene. We show that three mutations in particular occur with high frequency in the viral nucleoprotein (NP) protein (G102R, M105K and D375N) in a specific structural area upon in vivo adaptation. Moreover, our findings suggest that the adaptive NP mutations mediate viral escape from importin-α7 requirement likely due to the utilization of alternative interaction sites in NP beyond the classical nuclear localization signal. However, viral escape from importin-α7 by mutations in NP is, at least in part, associated with reduced viral replication highlighting the crucial contribution of importin-α7 to replicative fitness in human cells.

Keywords: host-pathogen interaction; influenza virus; nuclear transport; protein-protein interaction; virus evolution.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Active Transport, Cell Nucleus
  • Animals
  • Cell Nucleus / metabolism
  • Cells, Cultured
  • Dogs
  • HEK293 Cells
  • Humans
  • Influenza A Virus, H1N1 Subtype / genetics
  • Influenza A Virus, H1N1 Subtype / metabolism
  • Influenza A Virus, H1N1 Subtype / physiology*
  • Karyopherins / metabolism*
  • Madin Darby Canine Kidney Cells
  • Mice
  • Mutation
  • Nuclear Localization Signals
  • Nucleoproteins / chemistry
  • Nucleoproteins / genetics
  • Nucleoproteins / metabolism*
  • Protein Binding
  • Viral Proteins / chemistry
  • Viral Proteins / genetics
  • Viral Proteins / metabolism*
  • Virus Replication*


  • Karyopherins
  • Nuclear Localization Signals
  • Nucleoproteins
  • Viral Proteins
  • Ipo7 protein, mouse