Interaction of Polymerase Subunit PB2 and NP with Importin α1 Is a Determinant of Host Range of Influenza A Virus

Gülsah Gabriel,Hans-Dieter Klenk,Astrid Herwig,Yoshihiro Kawaoka

doi:10.1371/journal.ppat.0040011

Gülsah Gabriel, Hans-Dieter Klenk + Show 2 more

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https://doi.org/10.1371/journal.ppat.0040011

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Journal: PLoS Pathogens	Publication Date: Feb 1, 2008
Citations: 359	License type: CC BY 4.0

Affiliation: Philipps University of Marburg

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 α1 in mammalian cells. Enhanced binding was paralleled by transient nuclear accumulation and cytoplasmic depletion of importin α1 as well as increased transport of PB2 and NP into the nucleus of mammalian cells. In avian cells, enhancement of importin α1 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.

Highlights

The natural host of influenza A viruses is waterfowl where these agents occur in large variety defined by 16 hemagglutinin and 9 neuraminidase subtypes
We show that adaptive mutations in polymerase subunits improve binding to importin a1 in mammalian, but not in avian cells
These observations demonstrate that the interaction of the viral polymerase with the nuclear import machinery is an important determinant of host range

Summary

Introduction

The natural host of influenza A viruses is waterfowl where these agents occur in large variety defined by 16 hemagglutinin and 9 neuraminidase subtypes. Avian influenza viruses are the source of devastating outbreaks in poultry. Because of their potential to cross species barriers, to adapt to new hosts, and to cause on rare occasions pandemics, they are a constant threat to human health [1]. As members of the Orthomyxoviridae family influenza A viruses have a segmented RNA genome of negative polarity. The eight segments are present in enveloped virus particles as ribonucleoprotein (RNP) complexes with the nucleocapsid protein (NP) and the three subunits of the RNA-dependent RNA-polymerase (PB1, PB2, PA). The polymerase is responsible for transcription and replication of the viral genome [2,3]

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