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Influenza virus infection induces the nuclear relocalization of the Hsp90 co-chaperone p23 and inhibits the glucocorticoid receptor response.

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.

SUBMITTER: Ge X

PROVIDER: S-EPMC3154441 | biostudies-literature | 2011

REPOSITORIES: biostudies-literature

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Influenza virus infection induces the nuclear relocalization of the Hsp90 co-chaperone p23 and inhibits the glucocorticoid receptor response.

Ge Xingyi X Rameix-Welti Marie-Anne MA Gault Elyanne E Chase Geoffrey G dos Santos Afonso Emmanuel E Picard Didier D Schwemmle Martin M Naffakh Nadia N

PloS one 20110810 8

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, asso ...[more]

PMID: 21853119

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Project description:Prostate cancer is an androgen receptor (AR)-dependent malignancy at initiation and progression, therefore hormone therapy is the primary line of systemic treatment. Despite initial disease regression, tumours inevitably recur and progress to an advanced castration-resistant state a major feature of which is metastasis to the bone. Up-regulation of AR cofactors and chaperones that overcome low hormone conditions to maintain basal AR activity has been postulated as a mechanism of therapy relapse. p23, an essential component of the apo-AR complex, acts also after ligand binding to increase AR transcriptional activity and target gene expression, partly by increasing chromatin-loaded holo-receptor-complexes. Immunohistochemical studies have demonstrated increased p23 expression in advanced prostate cancer. Here, we further characterise p23 roles in AR signalling and show that it modulates cytosolic AR levels in the absence of hormone, confirming a chaperoning function in the aporeceptor complex and suggesting p23 upregulates AR signalling at multiple stages. Moreover, p23 protein levels significantly increased upon treatment with not only androgen but also clinically relevant anti-androgens. This was in contrast to the HSP90 inhibitor 17-AAG, which did not modulate expression of the cochaperone - important given the HSP90-independent roles we and others have previously described for p23. Further, we demonstrate p23 is implicated in prostate cancer cell motility and in acquisition of invasiveness capacity through the expression of specific genes known to participate in cancer progression. This may drive metastatic processes in vivo since analysis of prostate tumour biopsies revealed that high nuclear p23 significantly correlated with shorter survival times and with development of metastases in patients with lower grade tumours. We propose that increased p23 expression may allow cells to acquire a more aggressive phenotype, contributing to disease progression, and that p23 is a plausible secondary target in combination with HSP90 inhibition as a potential therapy for advanced prostate cancer.

Dataset Information

Influenza virus infection induces the nuclear relocalization of the Hsp90 co-chaperone p23 and inhibits the glucocorticoid receptor response.

Publications

Influenza virus infection induces the nuclear relocalization of the Hsp90 co-chaperone p23 and inhibits the glucocorticoid receptor response.

Similar Datasets

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