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

Abstract

Summary: 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. : Influenza virus circulating in diverse bird species requires the host co-factor ANP32A. Alternative splicing of an avian-signature exon in ANP32A differentially stimulates the influenza polymerase. Baker et al. demonstrate the precise step at which ANP32A rescues an otherwise restricted polymerase and suggest that splice preferences can affect influenza virus evolution. Keywords: influenza virus, viral polymerase, ANP32A, splicing, viral host range