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P62/SQSTM1 binds with claudin-2 to target for selective autophagy in stressed intestinal epithelium

Impaired autophagy promotes Inflammatory Bowel Disease (IBD). Claudin-2 is upregulated in IBD however its role in the pathobiology remains uncertain due to its complex regulation, including by autophagy. Irrespective, claudin-2 expression protects mice from DSS colitis. This study was undertaken to...

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Autores principales: Ahmad, Rizwan, Kumar, Balawant, Tamang, Raju Lama, Talmon, Geoffrey A., Dhawan, Punita, Singh, Amar B.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10352296/
https://www.ncbi.nlm.nih.gov/pubmed/37460613
http://dx.doi.org/10.1038/s42003-023-05116-2
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author Ahmad, Rizwan
Kumar, Balawant
Tamang, Raju Lama
Talmon, Geoffrey A.
Dhawan, Punita
Singh, Amar B.
author_facet Ahmad, Rizwan
Kumar, Balawant
Tamang, Raju Lama
Talmon, Geoffrey A.
Dhawan, Punita
Singh, Amar B.
author_sort Ahmad, Rizwan
collection PubMed
description Impaired autophagy promotes Inflammatory Bowel Disease (IBD). Claudin-2 is upregulated in IBD however its role in the pathobiology remains uncertain due to its complex regulation, including by autophagy. Irrespective, claudin-2 expression protects mice from DSS colitis. This study was undertaken to examine if an interplay between autophagy and claudin-2 protects from colitis and associated epithelial injury. Crypt culture and intestinal epithelial cells (IECs) are subjected to stress, including starvation or DSS, the chemical that induces colitis in-vivo. Autophagy flux, cell survival, co-immunoprecipitation, proximity ligation assay, and gene mutational studies are performed. These studies reveal that under colitis/stress conditions, claudin-2 undergoes polyubiquitination and P62/SQSTM1-assisted degradation through autophagy. Inhibiting autophagy-mediated claudin-2 degradation promotes cell death and thus suggest that claudin-2 degradation promotes autophagy flux to promote cell survival. Overall, these data inform for the previously undescribed role for claudin-2 in facilitating IECs survival under stress conditions, which can be harnessed for therapeutic advantages.
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spelling pubmed-103522962023-07-19 P62/SQSTM1 binds with claudin-2 to target for selective autophagy in stressed intestinal epithelium Ahmad, Rizwan Kumar, Balawant Tamang, Raju Lama Talmon, Geoffrey A. Dhawan, Punita Singh, Amar B. Commun Biol Article Impaired autophagy promotes Inflammatory Bowel Disease (IBD). Claudin-2 is upregulated in IBD however its role in the pathobiology remains uncertain due to its complex regulation, including by autophagy. Irrespective, claudin-2 expression protects mice from DSS colitis. This study was undertaken to examine if an interplay between autophagy and claudin-2 protects from colitis and associated epithelial injury. Crypt culture and intestinal epithelial cells (IECs) are subjected to stress, including starvation or DSS, the chemical that induces colitis in-vivo. Autophagy flux, cell survival, co-immunoprecipitation, proximity ligation assay, and gene mutational studies are performed. These studies reveal that under colitis/stress conditions, claudin-2 undergoes polyubiquitination and P62/SQSTM1-assisted degradation through autophagy. Inhibiting autophagy-mediated claudin-2 degradation promotes cell death and thus suggest that claudin-2 degradation promotes autophagy flux to promote cell survival. Overall, these data inform for the previously undescribed role for claudin-2 in facilitating IECs survival under stress conditions, which can be harnessed for therapeutic advantages. Nature Publishing Group UK 2023-07-17 /pmc/articles/PMC10352296/ /pubmed/37460613 http://dx.doi.org/10.1038/s42003-023-05116-2 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 license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license 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 license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Ahmad, Rizwan
Kumar, Balawant
Tamang, Raju Lama
Talmon, Geoffrey A.
Dhawan, Punita
Singh, Amar B.
P62/SQSTM1 binds with claudin-2 to target for selective autophagy in stressed intestinal epithelium
title P62/SQSTM1 binds with claudin-2 to target for selective autophagy in stressed intestinal epithelium
title_full P62/SQSTM1 binds with claudin-2 to target for selective autophagy in stressed intestinal epithelium
title_fullStr P62/SQSTM1 binds with claudin-2 to target for selective autophagy in stressed intestinal epithelium
title_full_unstemmed P62/SQSTM1 binds with claudin-2 to target for selective autophagy in stressed intestinal epithelium
title_short P62/SQSTM1 binds with claudin-2 to target for selective autophagy in stressed intestinal epithelium
title_sort p62/sqstm1 binds with claudin-2 to target for selective autophagy in stressed intestinal epithelium
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10352296/
https://www.ncbi.nlm.nih.gov/pubmed/37460613
http://dx.doi.org/10.1038/s42003-023-05116-2
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