title: Glucocorticoids alleviate intestinal ER stress by enhancing protein folding and degradation of misfolded proteins.
abstract: 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.
authors: Immunity, Infection and Inflammation Program, Mater Medical Research Institute, Mater Health Services, South Brisbane, Queensland 4101, Australia.
authors: Indrajit
authors: I
authors: Das
authors: Chin Wen
authors: CW
authors: Png
authors: Iulia
authors: I
authors: Oancea
authors: Sumaira Z
authors: SZ
authors: Hasnain
authors: Rohan
authors: R
authors: Lourie
authors: Martina
authors: M
authors: Proctor
authors: Rajaraman D
authors: RD
authors: Eri
authors: Yong
authors: Y
authors: Sheng
authors: Denis I
authors: DI
authors: Crane
authors: Timothy H
authors: TH
authors: Florin
authors: Michael A
authors: MA
authors: McGuckin
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D059865:Endoplasmic Reticulum Stress / Q000235:genetics / Q000502:physiology*; D004847:Epithelial Cells / Q000378:metabolism; D005260:Female; D005938:Glucocorticoids / Q000235:genetics / Q000378:metabolism*; D005947:Glucose / Q000235:genetics / Q000378:metabolism; D006031:Glycosylation; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000378:metabolism; D007413:Intestinal Mucosa / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D055262:Mucin-2 / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D017510:Protein Folding; D059748:Proteolysis; D011965:Receptors, Glucocorticoid / Q000235:genetics / Q000378:metabolism; D056811:Unfolded Protein Response / Q000235:genetics / Q000502:physiology*; D015854:Up-Regulation
chemical_list: C486654:EDEM1 protein, human; D005938:Glucocorticoids; D008565:Membrane Proteins; C524626:Muc2 protein, mouse; D055262:Mucin-2; D016328:NF-kappa B; D011965:Receptors, Glucocorticoid; D005947:Glucose; D002118:Calcium
references: Proc Natl Acad Sci U S A. 2012 Apr 10;109(15):E869-78
references: 22315414
references: Mol Endocrinol. 2005 Apr;19(4):885-97
references: 15591535
references: Inflammation. 2012 Jun;35(3):841-9
references: 21922249
references: Mol Cell Biol. 2002 Nov;22(22):7802-11
references: 12391149
references: J Pediatr Gastroenterol Nutr. 1985 Dec;4(6):893-901
references: 4067777
references: Cell. 2008 Sep 5;134(5):743-56
references: 18775308
references: Am J Physiol. 1995 Apr;268(4 Pt 1):L683-90
references: 7537465
references: Biochem Biophys Res Commun. 2004 Apr 30;317(2):390-6
references: 15063770
references: J Clin Invest. 2007 Apr;117(4):978-88
references: 17347682
references: J Virol. 2004 Nov;78(21):12071-4
references: 15479849
references: Cell Host Microbe. 2012 Feb 16;11(2):140-52
references: 22341463
references: Nat Med. 2011 Sep 04;17(10):1225-7
references: 21892181
references: Chin Med J (Engl). 2011 Jan;124(1):38-44
references: 21362305
references: J Virol. 2008 Nov;82(21):10375-85
references: 18768989
references: Pediatr Res. 2001 Jun;49(6):782-8
references: 11385138
references: Semin Cell Dev Biol. 2007 Dec;18(6):716-31
references: 18023214
references: J Clin Invest. 2001 Mar;107(5):585-93
references: 11238559
references: Gastroenterology. 2013 Feb;144(2):357-368.e9
references: 23123183
references: Hum Pathol. 1980 Nov;11(6):620-34
references: 6161074
references: J Endocrinol. 2011 Apr;209(1):105-14
references: 21282255
references: Mucosal Immunol. 2011 May;4(3):354-64
references: 21107311
references: Antioxid Redox Signal. 2009 Sep;11(9):2279-87
references: 19485711
references: FEBS Lett. 2007 Jul 31;581(19):3658-64
references: 17499246
references: J Biol Chem. 2006 Feb 17;281(7):4467-76
references: 16365039
references: PLoS Med. 2008 Mar 4;5(3):e54
references: 18318598
references: Proc Natl Acad Sci U S A. 2007 Aug 7;104(32):13098-103
references: 17670946
references: J Exp Med. 2006 Sep 4;203(9):2057-62
references: 16923850
references: Am J Anat. 1983 May;167(1):95-117
references: 6869312
references: J Clin Invest. 2002 Nov;110(10):1389-98
references: 12438434
references: Exp Cell Res. 2010 Feb 1;316(3):452-65
references: 19786015
references: J Vet Med Sci. 2009 Jun;71(6):801-5
references: 19578292
references: Proc Natl Acad Sci U S A. 2009 Apr 28;106(17):6950-5
references: 19359471
references: Clin Sci (Lond). 2009 Sep 28;118(1):19-29
references: 19780718
references: Am J Physiol Gastrointest Liver Physiol. 2010 Jun;298(6):G820-32
references: 20338921
references: Nat Rev Mol Cell Biol. 2008 Dec;9(12):944-57
references: 19002207
references: J Biol Chem. 1990 Jul 5;265(19):10893-9
references: 2162823
references: Inflamm Bowel Dis. 2009 Jan;15(1):100-13
references: 18623167
references: Gastroenterology. 2007 Jan;132(1):190-207
references: 17241871
references: Immunol Cell Biol. 2012 Mar;90(3):260-70
references: 22249202
references: J Exp Med. 2004 Dec 20;200(12):1635-46
references: 15596520
references: Physiol Rev. 2006 Oct;86(4):1133-49
references: 17015486
references: Aliment Pharmacol Ther. 2007 Jul 1;26(1):21-9
references: 17555418
references: Biochim Biophys Acta. 2002 Apr 12;1574(3):329-36
references: 11997099
references: J Biol Chem. 2005 Oct 7;280(40):33917-25
references: 16107336
references: Mutat Res. 2005 Jan 6;569(1-2):29-63
references: 15603751
references: Gastroenterology. 2009 Oct;137(4):1333-45.e1-3
references: 19549527
references: Int J Tissue React. 1986;8(1):79-84
references: 3949447
references: Acta Biochim Biophys Sin (Shanghai). 2009 Sep;41(9):781-91
references: 19727527
references: Proc Natl Acad Sci U S A. 2009 Mar 3;106(9):3300-5
references: 19202076
references: Gastroenterology. 2010 Feb;138(2):636-48, 648.e1-12
references: 19818784
references: Clin Sci (Lond). 1998 Jun;94(6):557-72
references: 9854452
references: FASEB J. 2008 Dec;22(12):4117-25
references: 18711026
references: Eur J Immunol. 2006 Aug;36(8):2139-49
references: 16841298
references: J Virol. 2007 Oct;81(20):10849-60
references: 17686866
references: Cell. 1995 May 5;81(3):425-33
references: 7736594
references: Oncogene. 2011 May 26;30(21):2411-9
references: 21258413
references: Kidney Int. 2006 Apr;69(8):1350-9
references: 16531978