Differential Splicing of ANP32A in Birds Alters Its Ability to Stimulate RNA Synthesis by Restricted Influenza Polymerase

Cell Rep. 2018 Sep 4;24(10):2581-2588.e4. doi: 10.1016/j.celrep.2018.08.012.

Abstract

Adaptation of viruses to their hosts can result in specialization and a restricted host range. Species-specific polymorphisms in the influenza virus polymerase restrict its host range during transmission from birds to mammals. ANP32A was recently identified as a cellular co-factor affecting polymerase adaption and activity. Avian influenza polymerases require ANP32A containing an insertion resulting from an exon duplication uniquely encoded in birds. Here we find that natural splice variants surrounding this exon create avian ANP32A proteins with distinct effects on polymerase activity. We demonstrate species-independent direct interactions between all ANP32A variants and the PB2 polymerase subunit. This interaction is enhanced in the presence of viral genomic RNA. In contrast, only avian ANP32A restored ribonucleoprotein complex assembly for a restricted polymerase by enhancing RNA synthesis. Our data suggest that ANP32A splicing variation among birds differentially affects viral replication, polymerase adaption, and the potential of avian hosts to be reservoirs.

Keywords: ANP32A; influenza virus; splicing; viral host range; viral polymerase.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Birds
  • Cell Line
  • Exons / genetics
  • Fluorescent Antibody Technique
  • Humans
  • Immunoprecipitation
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Orthomyxoviridae / genetics*
  • Orthomyxoviridae / pathogenicity*
  • Protein Binding / genetics
  • Protein Binding / physiology
  • RNA Splicing / genetics*
  • RNA, Viral / genetics
  • RNA, Viral / metabolism
  • Viral Proteins / genetics
  • Viral Proteins / metabolism*

Substances

  • Intracellular Signaling Peptides and Proteins
  • PB2 protein, influenza virus
  • RNA, Viral
  • Viral Proteins