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Protocadherin 20 maintains intestinal barrier function to protect against Crohn’s disease by targeting ATF6
BACKGROUND: Intestinal barrier dysfunction plays a central role in the pathological onset of Crohn’s disease. We identify the cadherin superfamily member protocadherin 20 (PCDH20) as a crucial factor in Crohn’s disease. Here we describe the function of PCDH20 and its mechanisms in gut homeostasis, b...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10320870/ https://www.ncbi.nlm.nih.gov/pubmed/37407995 http://dx.doi.org/10.1186/s13059-023-02991-0 |
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author | Huang, Shanshan Xie, Zhuo Han, Jing Wang, Huiling Yang, Guang Li, Manying Zhou, Gaoshi Wang, Ying Li, Lixuan Li, Li Zeng, Zhirong Yu, Jun Chen, Minhu Zhang, Shenghong |
author_facet | Huang, Shanshan Xie, Zhuo Han, Jing Wang, Huiling Yang, Guang Li, Manying Zhou, Gaoshi Wang, Ying Li, Lixuan Li, Li Zeng, Zhirong Yu, Jun Chen, Minhu Zhang, Shenghong |
author_sort | Huang, Shanshan |
collection | PubMed |
description | BACKGROUND: Intestinal barrier dysfunction plays a central role in the pathological onset of Crohn’s disease. We identify the cadherin superfamily member protocadherin 20 (PCDH20) as a crucial factor in Crohn’s disease. Here we describe the function of PCDH20 and its mechanisms in gut homeostasis, barrier integrity, and Crohn’s disease development. RESULTS: PCDH20 mRNA and protein expression is significantly downregulated in the colonic epithelium of Crohn’s disease patients and mice with induced colitis compared with controls. In mice, intestinal-specific Pcdh20 knockout causes defects in enterocyte proliferation and differentiation, while causing morphological abnormalities. Specifically, the deletion disrupts barrier integrity by unzipping adherens junctions via β-catenin regulation and p120-catenin phosphorylation, thus aggravating colitis in DSS- and TNBS-induced colitis mouse models. Furthermore, we identify activating transcription factor 6 (ATF6), a key chaperone of endoplasmic reticulum stress, as a functional downstream effector of PCDH20. By administering a selective ATF6 activator, the impairment of intestinal barrier integrity and dysregulation of CHOP/β-catenin/p-p120-catenin pathway was reversed in Pcdh20-ablated mice with colitis and PCDH20-deficient colonic cell lines. CONCLUSIONS: PCDH20 is an essential factor in maintaining intestinal epithelial homeostasis and barrier integrity. Specifically, PCDH20 helps to protect against colitis by tightening adherens junctions through the ATF6/CHOP/β-catenin/p-p120-catenin axis. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13059-023-02991-0. |
format | Online Article Text |
id | pubmed-10320870 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-103208702023-07-06 Protocadherin 20 maintains intestinal barrier function to protect against Crohn’s disease by targeting ATF6 Huang, Shanshan Xie, Zhuo Han, Jing Wang, Huiling Yang, Guang Li, Manying Zhou, Gaoshi Wang, Ying Li, Lixuan Li, Li Zeng, Zhirong Yu, Jun Chen, Minhu Zhang, Shenghong Genome Biol Research BACKGROUND: Intestinal barrier dysfunction plays a central role in the pathological onset of Crohn’s disease. We identify the cadherin superfamily member protocadherin 20 (PCDH20) as a crucial factor in Crohn’s disease. Here we describe the function of PCDH20 and its mechanisms in gut homeostasis, barrier integrity, and Crohn’s disease development. RESULTS: PCDH20 mRNA and protein expression is significantly downregulated in the colonic epithelium of Crohn’s disease patients and mice with induced colitis compared with controls. In mice, intestinal-specific Pcdh20 knockout causes defects in enterocyte proliferation and differentiation, while causing morphological abnormalities. Specifically, the deletion disrupts barrier integrity by unzipping adherens junctions via β-catenin regulation and p120-catenin phosphorylation, thus aggravating colitis in DSS- and TNBS-induced colitis mouse models. Furthermore, we identify activating transcription factor 6 (ATF6), a key chaperone of endoplasmic reticulum stress, as a functional downstream effector of PCDH20. By administering a selective ATF6 activator, the impairment of intestinal barrier integrity and dysregulation of CHOP/β-catenin/p-p120-catenin pathway was reversed in Pcdh20-ablated mice with colitis and PCDH20-deficient colonic cell lines. CONCLUSIONS: PCDH20 is an essential factor in maintaining intestinal epithelial homeostasis and barrier integrity. Specifically, PCDH20 helps to protect against colitis by tightening adherens junctions through the ATF6/CHOP/β-catenin/p-p120-catenin axis. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13059-023-02991-0. BioMed Central 2023-07-05 /pmc/articles/PMC10320870/ /pubmed/37407995 http://dx.doi.org/10.1186/s13059-023-02991-0 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/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data. |
spellingShingle | Research Huang, Shanshan Xie, Zhuo Han, Jing Wang, Huiling Yang, Guang Li, Manying Zhou, Gaoshi Wang, Ying Li, Lixuan Li, Li Zeng, Zhirong Yu, Jun Chen, Minhu Zhang, Shenghong Protocadherin 20 maintains intestinal barrier function to protect against Crohn’s disease by targeting ATF6 |
title | Protocadherin 20 maintains intestinal barrier function to protect against Crohn’s disease by targeting ATF6 |
title_full | Protocadherin 20 maintains intestinal barrier function to protect against Crohn’s disease by targeting ATF6 |
title_fullStr | Protocadherin 20 maintains intestinal barrier function to protect against Crohn’s disease by targeting ATF6 |
title_full_unstemmed | Protocadherin 20 maintains intestinal barrier function to protect against Crohn’s disease by targeting ATF6 |
title_short | Protocadherin 20 maintains intestinal barrier function to protect against Crohn’s disease by targeting ATF6 |
title_sort | protocadherin 20 maintains intestinal barrier function to protect against crohn’s disease by targeting atf6 |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10320870/ https://www.ncbi.nlm.nih.gov/pubmed/37407995 http://dx.doi.org/10.1186/s13059-023-02991-0 |
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