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


Das, I and Png, CW and Oancea, I and Hasnain, SZ and Lourie, R and Proctor, M and Eri, RD and Sheng, Y and Crane, DI and Florin, TH and McGuckin, MA, Glucocorticoids alleviate intestinal ER stress by enhancing protein folding and degradation of misfolded proteins, The Journal of Experimental Medicine, 210, (6) pp. 1201-1216. ISSN 0022-1007 (2013) [Refereed Article]

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Copyright 2013 The Rockefeller University Press

DOI: doi:10.1084/jem.20121268


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 Ca2+ 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.

Item Details

Item Type:Refereed Article
Research Division:Biological Sciences
Research Group:Biochemistry and cell biology
Research Field:Biochemistry and cell biology not elsewhere classified
Objective Division:Health
Objective Group:Clinical health
Objective Field:Clinical health not elsewhere classified
UTAS Author:Eri, RD (Associate Professor Raj Eri)
ID Code:84517
Year Published:2013
Web of Science® Times Cited:63
Deposited By:Health Sciences A
Deposited On:2013-05-16
Last Modified:2014-05-23

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