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

Steven F Baker; Mitchell P Ledwith; Andrew Mehle

doi:10.1016/j.celrep.2018.08.012

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.

Authors

Steven F Baker¹, Mitchell P Ledwith², Andrew Mehle³

Affiliations

¹ Department of Medical Microbiology and Immunology, University of Wisconsin-Madison, Madison, WI, USA.
² Department of Medical Microbiology and Immunology, University of Wisconsin-Madison, Madison, WI, USA; Graduate Program in Cellular and Molecular Biology, University of Wisconsin-Madison, Madison, WI, USA.
³ Department of Medical Microbiology and Immunology, University of Wisconsin-Madison, Madison, WI, USA. Electronic address: [email protected].

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

Abstract

Publication types

MeSH terms

Substances

Grants and funding