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PATJ inhibits histone deacetylase 7 to control tight junction formation and cell polarity

The conserved multiple PDZ-domain containing protein PATJ stabilizes the Crumbs-Pals1 complex to regulate apical-basal polarity and tight junction formation in epithelial cells. However, the molecular mechanism of PATJ’s function in these processes is still unclear. In this study, we demonstrate tha...

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Autores principales: Fiedler, Julia, Moennig, Thomas, Hinrichs, Johanna H., Weber, Annika, Wagner, Thomas, Hemmer, Tim, Schröter, Rita, Weide, Thomas, Epting, Daniel, Bergmann, Carsten, Nedvetsky, Pavel, Krahn, Michael P.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer International Publishing 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10600057/
https://www.ncbi.nlm.nih.gov/pubmed/37878054
http://dx.doi.org/10.1007/s00018-023-04994-3
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author Fiedler, Julia
Moennig, Thomas
Hinrichs, Johanna H.
Weber, Annika
Wagner, Thomas
Hemmer, Tim
Schröter, Rita
Weide, Thomas
Epting, Daniel
Bergmann, Carsten
Nedvetsky, Pavel
Krahn, Michael P.
author_facet Fiedler, Julia
Moennig, Thomas
Hinrichs, Johanna H.
Weber, Annika
Wagner, Thomas
Hemmer, Tim
Schröter, Rita
Weide, Thomas
Epting, Daniel
Bergmann, Carsten
Nedvetsky, Pavel
Krahn, Michael P.
author_sort Fiedler, Julia
collection PubMed
description The conserved multiple PDZ-domain containing protein PATJ stabilizes the Crumbs-Pals1 complex to regulate apical-basal polarity and tight junction formation in epithelial cells. However, the molecular mechanism of PATJ’s function in these processes is still unclear. In this study, we demonstrate that knockout of PATJ in epithelial cells results in tight junction defects as well as in a disturbed apical-basal polarity and impaired lumen formation in three-dimensional cyst assays. Mechanistically, we found PATJ to associate with and inhibit histone deacetylase 7 (HDAC7). Inhibition or downregulation of HDAC7 restores polarity and lumen formation. Gene expression analysis of PATJ-deficient cells revealed an impaired expression of genes involved in cell junction assembly and membrane organization, which is rescued by the downregulation of HDAC7. Notably, the function of PATJ regulating HDAC7-dependent cilia formation does not depend on its canonical interaction partner, Pals1, indicating a new role of PATJ, which is distinct from its function in the Crumbs complex. By contrast, polarity and lumen phenotypes observed in Pals1- and PATJ-deficient epithelial cells can be rescued by inhibition of HDAC7, suggesting that the main function of this polarity complex in this process is to modulate the transcriptional profile of epithelial cells by inhibiting HDAC7. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00018-023-04994-3.
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spelling pubmed-106000572023-10-27 PATJ inhibits histone deacetylase 7 to control tight junction formation and cell polarity Fiedler, Julia Moennig, Thomas Hinrichs, Johanna H. Weber, Annika Wagner, Thomas Hemmer, Tim Schröter, Rita Weide, Thomas Epting, Daniel Bergmann, Carsten Nedvetsky, Pavel Krahn, Michael P. Cell Mol Life Sci Original Article The conserved multiple PDZ-domain containing protein PATJ stabilizes the Crumbs-Pals1 complex to regulate apical-basal polarity and tight junction formation in epithelial cells. However, the molecular mechanism of PATJ’s function in these processes is still unclear. In this study, we demonstrate that knockout of PATJ in epithelial cells results in tight junction defects as well as in a disturbed apical-basal polarity and impaired lumen formation in three-dimensional cyst assays. Mechanistically, we found PATJ to associate with and inhibit histone deacetylase 7 (HDAC7). Inhibition or downregulation of HDAC7 restores polarity and lumen formation. Gene expression analysis of PATJ-deficient cells revealed an impaired expression of genes involved in cell junction assembly and membrane organization, which is rescued by the downregulation of HDAC7. Notably, the function of PATJ regulating HDAC7-dependent cilia formation does not depend on its canonical interaction partner, Pals1, indicating a new role of PATJ, which is distinct from its function in the Crumbs complex. By contrast, polarity and lumen phenotypes observed in Pals1- and PATJ-deficient epithelial cells can be rescued by inhibition of HDAC7, suggesting that the main function of this polarity complex in this process is to modulate the transcriptional profile of epithelial cells by inhibiting HDAC7. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00018-023-04994-3. Springer International Publishing 2023-10-25 2023 /pmc/articles/PMC10600057/ /pubmed/37878054 http://dx.doi.org/10.1007/s00018-023-04994-3 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Original Article
Fiedler, Julia
Moennig, Thomas
Hinrichs, Johanna H.
Weber, Annika
Wagner, Thomas
Hemmer, Tim
Schröter, Rita
Weide, Thomas
Epting, Daniel
Bergmann, Carsten
Nedvetsky, Pavel
Krahn, Michael P.
PATJ inhibits histone deacetylase 7 to control tight junction formation and cell polarity
title PATJ inhibits histone deacetylase 7 to control tight junction formation and cell polarity
title_full PATJ inhibits histone deacetylase 7 to control tight junction formation and cell polarity
title_fullStr PATJ inhibits histone deacetylase 7 to control tight junction formation and cell polarity
title_full_unstemmed PATJ inhibits histone deacetylase 7 to control tight junction formation and cell polarity
title_short PATJ inhibits histone deacetylase 7 to control tight junction formation and cell polarity
title_sort patj inhibits histone deacetylase 7 to control tight junction formation and cell polarity
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10600057/
https://www.ncbi.nlm.nih.gov/pubmed/37878054
http://dx.doi.org/10.1007/s00018-023-04994-3
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