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Virulence Factors of Pseudomonas aeruginosa Induce Both the Unfolded Protein and Integrated Stress Responses in Airway Epithelial Cells

Pseudomonas aeruginosa infection can be disastrous in chronic lung diseases such as cystic fibrosis and chronic obstructive pulmonary disease. Its toxic effects are largely mediated by secreted virulence factors including pyocyanin, elastase and alkaline protease (AprA). Efficient functioning of the...

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Autores principales: van ‘t Wout, Emily F. A., van Schadewijk, Annemarie, van Boxtel, Ria, Dalton, Lucy E., Clarke, Hanna J., Tommassen, Jan, Marciniak, Stefan J., Hiemstra, Pieter S.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4471080/
https://www.ncbi.nlm.nih.gov/pubmed/26083346
http://dx.doi.org/10.1371/journal.ppat.1004946
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author van ‘t Wout, Emily F. A.
van Schadewijk, Annemarie
van Boxtel, Ria
Dalton, Lucy E.
Clarke, Hanna J.
Tommassen, Jan
Marciniak, Stefan J.
Hiemstra, Pieter S.
author_facet van ‘t Wout, Emily F. A.
van Schadewijk, Annemarie
van Boxtel, Ria
Dalton, Lucy E.
Clarke, Hanna J.
Tommassen, Jan
Marciniak, Stefan J.
Hiemstra, Pieter S.
author_sort van ‘t Wout, Emily F. A.
collection PubMed
description Pseudomonas aeruginosa infection can be disastrous in chronic lung diseases such as cystic fibrosis and chronic obstructive pulmonary disease. Its toxic effects are largely mediated by secreted virulence factors including pyocyanin, elastase and alkaline protease (AprA). Efficient functioning of the endoplasmic reticulum (ER) is crucial for cell survival and appropriate immune responses, while an excess of unfolded proteins within the ER leads to “ER stress” and activation of the “unfolded protein response” (UPR). Bacterial infection and Toll-like receptor activation trigger the UPR most likely due to the increased demand for protein folding of inflammatory mediators. In this study, we show that cell-free conditioned medium of the PAO1 strain of P. aeruginosa, containing secreted virulence factors, induces ER stress in primary bronchial epithelial cells as evidenced by splicing of XBP1 mRNA and induction of CHOP, GRP78 and GADD34 expression. Most aspects of the ER stress response were dependent on TAK1 and p38 MAPK, except for the induction of GADD34 mRNA. Using various mutant strains and purified virulence factors, we identified pyocyanin and AprA as inducers of ER stress. However, the induction of GADD34 was mediated by an ER stress-independent integrated stress response (ISR) which was at least partly dependent on the iron-sensing eIF2α kinase HRI. Our data strongly suggest that this increased GADD34 expression served to protect against Pseudomonas-induced, iron-sensitive cell cytotoxicity. In summary, virulence factors from P. aeruginosa induce ER stress in airway epithelial cells and also trigger the ISR to improve cell survival of the host.
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spelling pubmed-44710802015-06-29 Virulence Factors of Pseudomonas aeruginosa Induce Both the Unfolded Protein and Integrated Stress Responses in Airway Epithelial Cells van ‘t Wout, Emily F. A. van Schadewijk, Annemarie van Boxtel, Ria Dalton, Lucy E. Clarke, Hanna J. Tommassen, Jan Marciniak, Stefan J. Hiemstra, Pieter S. PLoS Pathog Research Article Pseudomonas aeruginosa infection can be disastrous in chronic lung diseases such as cystic fibrosis and chronic obstructive pulmonary disease. Its toxic effects are largely mediated by secreted virulence factors including pyocyanin, elastase and alkaline protease (AprA). Efficient functioning of the endoplasmic reticulum (ER) is crucial for cell survival and appropriate immune responses, while an excess of unfolded proteins within the ER leads to “ER stress” and activation of the “unfolded protein response” (UPR). Bacterial infection and Toll-like receptor activation trigger the UPR most likely due to the increased demand for protein folding of inflammatory mediators. In this study, we show that cell-free conditioned medium of the PAO1 strain of P. aeruginosa, containing secreted virulence factors, induces ER stress in primary bronchial epithelial cells as evidenced by splicing of XBP1 mRNA and induction of CHOP, GRP78 and GADD34 expression. Most aspects of the ER stress response were dependent on TAK1 and p38 MAPK, except for the induction of GADD34 mRNA. Using various mutant strains and purified virulence factors, we identified pyocyanin and AprA as inducers of ER stress. However, the induction of GADD34 was mediated by an ER stress-independent integrated stress response (ISR) which was at least partly dependent on the iron-sensing eIF2α kinase HRI. Our data strongly suggest that this increased GADD34 expression served to protect against Pseudomonas-induced, iron-sensitive cell cytotoxicity. In summary, virulence factors from P. aeruginosa induce ER stress in airway epithelial cells and also trigger the ISR to improve cell survival of the host. Public Library of Science 2015-06-17 /pmc/articles/PMC4471080/ /pubmed/26083346 http://dx.doi.org/10.1371/journal.ppat.1004946 Text en © 2015 van ‘t Wout et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
van ‘t Wout, Emily F. A.
van Schadewijk, Annemarie
van Boxtel, Ria
Dalton, Lucy E.
Clarke, Hanna J.
Tommassen, Jan
Marciniak, Stefan J.
Hiemstra, Pieter S.
Virulence Factors of Pseudomonas aeruginosa Induce Both the Unfolded Protein and Integrated Stress Responses in Airway Epithelial Cells
title Virulence Factors of Pseudomonas aeruginosa Induce Both the Unfolded Protein and Integrated Stress Responses in Airway Epithelial Cells
title_full Virulence Factors of Pseudomonas aeruginosa Induce Both the Unfolded Protein and Integrated Stress Responses in Airway Epithelial Cells
title_fullStr Virulence Factors of Pseudomonas aeruginosa Induce Both the Unfolded Protein and Integrated Stress Responses in Airway Epithelial Cells
title_full_unstemmed Virulence Factors of Pseudomonas aeruginosa Induce Both the Unfolded Protein and Integrated Stress Responses in Airway Epithelial Cells
title_short Virulence Factors of Pseudomonas aeruginosa Induce Both the Unfolded Protein and Integrated Stress Responses in Airway Epithelial Cells
title_sort virulence factors of pseudomonas aeruginosa induce both the unfolded protein and integrated stress responses in airway epithelial cells
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4471080/
https://www.ncbi.nlm.nih.gov/pubmed/26083346
http://dx.doi.org/10.1371/journal.ppat.1004946
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