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Chk2-dependent HuR phosphorylation regulates occludin mRNA translation and epithelial barrier function

Occludin is a transmembrane tight junction (TJ) protein that plays an important role in TJ assembly and regulation of the epithelial barrier function, but the mechanisms underlying its post-transcriptional regulation are unknown. The RNA-binding protein HuR modulates the stability and translation of...

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Autores principales: Yu, Ting-Xi, Wang, Peng-Yuan, Rao, Jaladanki N., Zou, Tongtong, Liu, Lan, Xiao, Lan, Gorospe, Myriam, Wang, Jian-Ying
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2011
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3201881/
https://www.ncbi.nlm.nih.gov/pubmed/21745814
http://dx.doi.org/10.1093/nar/gkr567
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author Yu, Ting-Xi
Wang, Peng-Yuan
Rao, Jaladanki N.
Zou, Tongtong
Liu, Lan
Xiao, Lan
Gorospe, Myriam
Wang, Jian-Ying
author_facet Yu, Ting-Xi
Wang, Peng-Yuan
Rao, Jaladanki N.
Zou, Tongtong
Liu, Lan
Xiao, Lan
Gorospe, Myriam
Wang, Jian-Ying
author_sort Yu, Ting-Xi
collection PubMed
description Occludin is a transmembrane tight junction (TJ) protein that plays an important role in TJ assembly and regulation of the epithelial barrier function, but the mechanisms underlying its post-transcriptional regulation are unknown. The RNA-binding protein HuR modulates the stability and translation of many target mRNAs. Here, we investigated the role of HuR in the regulation of occludin expression and therefore in the intestinal epithelial barrier function. HuR bound the 3′-untranslated region of the occludin mRNA and enhanced occludin translation. HuR association with the occludin mRNA depended on Chk2-dependent HuR phosphorylation. Reduced HuR phosphorylation by Chk2 silencing or by reduction of Chk2 through polyamine depletion decreased HuR-binding to the occludin mRNA and repressed occludin translation, whereas Chk2 overexpression enhanced (HuR/occludin mRNA) association and stimulated occludin expression. In mice exposed to septic stress induced by cecal ligation and puncture, Chk2 levels in the intestinal mucosa decreased, associated with an inhibition of occludin expression and gut barrier dysfunction. These results indicate that HuR regulates occludin mRNA translation through Chk2-dependent HuR phosphorylation and that this influence is crucial for maintenance of the epithelial barrier integrity in the intestinal tract.
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spelling pubmed-32018812011-10-26 Chk2-dependent HuR phosphorylation regulates occludin mRNA translation and epithelial barrier function Yu, Ting-Xi Wang, Peng-Yuan Rao, Jaladanki N. Zou, Tongtong Liu, Lan Xiao, Lan Gorospe, Myriam Wang, Jian-Ying Nucleic Acids Res Molecular Biology Occludin is a transmembrane tight junction (TJ) protein that plays an important role in TJ assembly and regulation of the epithelial barrier function, but the mechanisms underlying its post-transcriptional regulation are unknown. The RNA-binding protein HuR modulates the stability and translation of many target mRNAs. Here, we investigated the role of HuR in the regulation of occludin expression and therefore in the intestinal epithelial barrier function. HuR bound the 3′-untranslated region of the occludin mRNA and enhanced occludin translation. HuR association with the occludin mRNA depended on Chk2-dependent HuR phosphorylation. Reduced HuR phosphorylation by Chk2 silencing or by reduction of Chk2 through polyamine depletion decreased HuR-binding to the occludin mRNA and repressed occludin translation, whereas Chk2 overexpression enhanced (HuR/occludin mRNA) association and stimulated occludin expression. In mice exposed to septic stress induced by cecal ligation and puncture, Chk2 levels in the intestinal mucosa decreased, associated with an inhibition of occludin expression and gut barrier dysfunction. These results indicate that HuR regulates occludin mRNA translation through Chk2-dependent HuR phosphorylation and that this influence is crucial for maintenance of the epithelial barrier integrity in the intestinal tract. Oxford University Press 2011-10 2011-07-09 /pmc/articles/PMC3201881/ /pubmed/21745814 http://dx.doi.org/10.1093/nar/gkr567 Text en © The Author(s) 2011. Published by Oxford University Press. http://creativecommons.org/licenses/by-nc/3.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Molecular Biology
Yu, Ting-Xi
Wang, Peng-Yuan
Rao, Jaladanki N.
Zou, Tongtong
Liu, Lan
Xiao, Lan
Gorospe, Myriam
Wang, Jian-Ying
Chk2-dependent HuR phosphorylation regulates occludin mRNA translation and epithelial barrier function
title Chk2-dependent HuR phosphorylation regulates occludin mRNA translation and epithelial barrier function
title_full Chk2-dependent HuR phosphorylation regulates occludin mRNA translation and epithelial barrier function
title_fullStr Chk2-dependent HuR phosphorylation regulates occludin mRNA translation and epithelial barrier function
title_full_unstemmed Chk2-dependent HuR phosphorylation regulates occludin mRNA translation and epithelial barrier function
title_short Chk2-dependent HuR phosphorylation regulates occludin mRNA translation and epithelial barrier function
title_sort chk2-dependent hur phosphorylation regulates occludin mrna translation and epithelial barrier function
topic Molecular Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3201881/
https://www.ncbi.nlm.nih.gov/pubmed/21745814
http://dx.doi.org/10.1093/nar/gkr567
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