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Glucocorticoids alleviate intestinal ER stress by enhancing protein folding and degradation of misfolded proteins

Endoplasmic reticulum (ER) stress in intestinal secretory cells has been linked with colitis in mice and inflammatory bowel disease (IBD). Endogenous intestinal glucocorticoids are important for homeostasis and glucocorticoid drugs are efficacious in IBD. In Winnie mice with intestinal ER stress cau...

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Autores principales: Das, Indrajit, Png, Chin Wen, Oancea, Iulia, Hasnain, Sumaira Z., Lourie, Rohan, Proctor, Martina, Eri, Rajaraman D., Sheng, Yong, Crane, Denis I., Florin, Timothy H., McGuckin, Michael A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3674691/
https://www.ncbi.nlm.nih.gov/pubmed/23650437
http://dx.doi.org/10.1084/jem.20121268
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author Das, Indrajit
Png, Chin Wen
Oancea, Iulia
Hasnain, Sumaira Z.
Lourie, Rohan
Proctor, Martina
Eri, Rajaraman D.
Sheng, Yong
Crane, Denis I.
Florin, Timothy H.
McGuckin, Michael A.
author_facet Das, Indrajit
Png, Chin Wen
Oancea, Iulia
Hasnain, Sumaira Z.
Lourie, Rohan
Proctor, Martina
Eri, Rajaraman D.
Sheng, Yong
Crane, Denis I.
Florin, Timothy H.
McGuckin, Michael A.
author_sort Das, Indrajit
collection PubMed
description Endoplasmic reticulum (ER) stress in intestinal secretory cells has been linked with colitis in mice and inflammatory bowel disease (IBD). Endogenous intestinal glucocorticoids are important for homeostasis and glucocorticoid drugs are efficacious in IBD. In Winnie mice with intestinal ER stress caused by misfolding of the Muc2 mucin, the glucocorticoid dexamethasone (DEX) suppressed ER stress and activation of the unfolded protein response (UPR), substantially restoring goblet cell Muc2 production. In mice lacking inflammation, a glucocorticoid receptor antagonist increased ER stress, and DEX suppressed ER stress induced by the N-glycosylation inhibitor, tunicamycin (Tm). In cultured human intestinal secretory cells, in a glucocorticoid receptor-dependent manner, DEX suppressed ER stress and UPR activation induced by blocking N-glycosylation, reducing ER Ca(2+) or depleting glucose. DEX up-regulated genes encoding chaperones and elements of ER-associated degradation (ERAD), including EDEM1. Silencing EDEM1 partially inhibited DEX’s suppression of misfolding-induced ER stress, showing that DEX enhances ERAD. DEX inhibited Tm-induced MUC2 precursor accumulation, promoted production of mature mucin, and restored ER exit and secretion of Winnie mutant recombinant Muc2 domains, consistent with enhanced protein folding. In IBD, glucocorticoids are likely to ameliorate ER stress by promoting correct folding of secreted proteins and enhancing removal of misfolded proteins from the ER.
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spelling pubmed-36746912013-12-03 Glucocorticoids alleviate intestinal ER stress by enhancing protein folding and degradation of misfolded proteins Das, Indrajit Png, Chin Wen Oancea, Iulia Hasnain, Sumaira Z. Lourie, Rohan Proctor, Martina Eri, Rajaraman D. Sheng, Yong Crane, Denis I. Florin, Timothy H. McGuckin, Michael A. J Exp Med Article Endoplasmic reticulum (ER) stress in intestinal secretory cells has been linked with colitis in mice and inflammatory bowel disease (IBD). Endogenous intestinal glucocorticoids are important for homeostasis and glucocorticoid drugs are efficacious in IBD. In Winnie mice with intestinal ER stress caused by misfolding of the Muc2 mucin, the glucocorticoid dexamethasone (DEX) suppressed ER stress and activation of the unfolded protein response (UPR), substantially restoring goblet cell Muc2 production. In mice lacking inflammation, a glucocorticoid receptor antagonist increased ER stress, and DEX suppressed ER stress induced by the N-glycosylation inhibitor, tunicamycin (Tm). In cultured human intestinal secretory cells, in a glucocorticoid receptor-dependent manner, DEX suppressed ER stress and UPR activation induced by blocking N-glycosylation, reducing ER Ca(2+) or depleting glucose. DEX up-regulated genes encoding chaperones and elements of ER-associated degradation (ERAD), including EDEM1. Silencing EDEM1 partially inhibited DEX’s suppression of misfolding-induced ER stress, showing that DEX enhances ERAD. DEX inhibited Tm-induced MUC2 precursor accumulation, promoted production of mature mucin, and restored ER exit and secretion of Winnie mutant recombinant Muc2 domains, consistent with enhanced protein folding. In IBD, glucocorticoids are likely to ameliorate ER stress by promoting correct folding of secreted proteins and enhancing removal of misfolded proteins from the ER. The Rockefeller University Press 2013-06-03 /pmc/articles/PMC3674691/ /pubmed/23650437 http://dx.doi.org/10.1084/jem.20121268 Text en © 2013 Das et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).
spellingShingle Article
Das, Indrajit
Png, Chin Wen
Oancea, Iulia
Hasnain, Sumaira Z.
Lourie, Rohan
Proctor, Martina
Eri, Rajaraman D.
Sheng, Yong
Crane, Denis I.
Florin, Timothy H.
McGuckin, Michael A.
Glucocorticoids alleviate intestinal ER stress by enhancing protein folding and degradation of misfolded proteins
title Glucocorticoids alleviate intestinal ER stress by enhancing protein folding and degradation of misfolded proteins
title_full Glucocorticoids alleviate intestinal ER stress by enhancing protein folding and degradation of misfolded proteins
title_fullStr Glucocorticoids alleviate intestinal ER stress by enhancing protein folding and degradation of misfolded proteins
title_full_unstemmed Glucocorticoids alleviate intestinal ER stress by enhancing protein folding and degradation of misfolded proteins
title_short Glucocorticoids alleviate intestinal ER stress by enhancing protein folding and degradation of misfolded proteins
title_sort glucocorticoids alleviate intestinal er stress by enhancing protein folding and degradation of misfolded proteins
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3674691/
https://www.ncbi.nlm.nih.gov/pubmed/23650437
http://dx.doi.org/10.1084/jem.20121268
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