Interaction of polymerase subunit PB2 and NP with importin alpha1 is a determinant of host range of influenza A virus

PLoS Pathog. 2008 Feb 8;4(2):e11. doi: 10.1371/journal.ppat.0040011.

Abstract

We have previously reported that mutations in the polymerase proteins PB1, PB2, PA, and the nucleocapsid protein NP resulting in enhanced transcription and replication activities in mammalian cells are responsible for the conversion of the avian influenza virus SC35 (H7N7) into the mouse-adapted variant SC35M. We show now that adaptive mutations D701N in PB2 and N319K in NP enhance binding of these proteins to importin alpha1 in mammalian cells. Enhanced binding was paralleled by transient nuclear accumulation and cytoplasmic depletion of importin alpha1 as well as increased transport of PB2 and NP into the nucleus of mammalian cells. In avian cells, enhancement of importin alpha1 binding and increased nuclear transport were not observed. These findings demonstrate that adaptation of the viral polymerase to the nuclear import machinery plays an important role in interspecies transmission of influenza virus.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, Viral / genetics
  • Antigens, Viral / metabolism*
  • Cell Line
  • Cell Nucleus / metabolism
  • Cell Nucleus / virology
  • Chick Embryo
  • Gene Expression Regulation, Viral
  • Host-Pathogen Interactions*
  • Humans
  • Influenza A Virus, H7N7 Subtype / pathogenicity
  • Influenza A Virus, H7N7 Subtype / physiology
  • Mutation
  • Peptide Fragments / genetics
  • Peptide Fragments / metabolism*
  • Protein Binding
  • RNA-Dependent RNA Polymerase / metabolism*
  • Viral Core Proteins / genetics
  • Viral Core Proteins / metabolism*
  • Viral Proteins / metabolism*
  • Virus Replication
  • alpha Karyopherins / genetics
  • alpha Karyopherins / metabolism*

Substances

  • Antigens, Viral
  • PB2 protein, Influenzavirus A
  • Peptide Fragments
  • Viral Core Proteins
  • Viral Proteins
  • alpha Karyopherins
  • karyopherin alpha 2
  • nucleoprotein (366-374), influenza virus
  • RNA-Dependent RNA Polymerase