Influenza Virus Infection Induces the Nuclear Relocalization of the Hsp90 Co-Chaperone p23 and Inhibits the Glucocorticoid Receptor Response

Xingyi Ge,Marie-Anne Rameix-Welti,Geoffrey Chase,Nadia Naffakh,Emmanuel Dos Santos Afonso,Didier Picard,Martin Schwemmle,Elyanne Gault,Paul Digard

doi:10.1371/journal.pone.0023368

Abstract

The genomic RNAs of influenza A viruses are associated with the viral polymerase subunits (PB1, PB2, PA) and nucleoprotein (NP), forming ribonucleoprotein complexes (RNPs). Transcription/replication of the viral genome occurs in the nucleus of infected cells. A role for Hsp90 in nuclear import and assembly of newly synthetized RNA-polymerase subunits has been proposed. Here we report that the p23 cochaperone of Hsp90, which plays a major role in glucocorticoid receptor folding and function, associates with influenza virus polymerase. We show that p23 is not essential for viral multiplication in cultured cells but relocalizes to the nucleus in influenza virus-infected cells, which may alter some functions of p23 and Hsp90. Moreover, we show that influenza virus infection inhibits glucocorticoid receptor-mediated gene transactivation, and that this negative effect can occur through a p23-independent pathway. Viral-induced inhibition of the glucocorticoid receptor response might be of significant importance regarding the physiopathology of influenza infections in vivo.

Highlights

The genome of influenza A viruses consists of eight molecules of single-stranded RNA of negative polarity
At late stages in infection, viral ribonucleoproteins (vRNPs) are exported from the nucleus to the cytoplasm, and assembly with the other viral proteins occurs at the plasma membrane
We report that the p23 cochaperone of Hsp90, which plays a major role in the folding and function of glucocorticoid receptors [16], associates with the viral polymerase and relocalizes to the nucleus in influenza virus-infected cells

Summary

Introduction

The genome of influenza A viruses consists of eight molecules of single-stranded RNA of negative polarity. Synthetised NP and polymerase subunits are imported from the cytoplasm into the nucleus to form new vRNPs. At late stages in infection, vRNPs are exported from the nucleus to the cytoplasm, and assembly with the other viral proteins occurs at the plasma membrane. The Hsp protein was found to interact with both PB1 and PB2 and to undergo nuclear relocalization in infected cells [5], suggesting that it could be involved in nuclear import of newly synthetised viral polymerase subunits. We report that the p23 cochaperone of Hsp, which plays a major role in the folding and function of glucocorticoid receptors [16], associates with the viral polymerase and relocalizes to the nucleus in influenza virus-infected cells. PLoS ONE | www.plosone.org p23 Association with Influenza Virus Polymerase glucocorticoid receptor-mediated signalling is impaired in influenza virus-infected cells

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Discussion