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dc.contributor.authorDas, Indrajit
dc.contributor.authorPng, Chin Wen
dc.contributor.authorOancea, Iulia
dc.contributor.authorHasnain, Sumaira Z
dc.contributor.authorLourie, Rohan
dc.contributor.authorProctor, Martina
dc.contributor.authorEri, Rajaraman D
dc.contributor.authorSheng, Yong
dc.contributor.authorCrane, Denis I
dc.contributor.authorFlorin, Timothy H
dc.contributor.authorMcGuckin, Michael A
dc.date.accessioned2017-05-03T11:02:03Z
dc.date.available2017-05-03T11:02:03Z
dc.date.issued2013
dc.date.modified2014-01-30T22:25:43Z
dc.identifier.issn0022-1007
dc.identifier.doi10.1084/jem.20121268
dc.identifier.urihttp://hdl.handle.net/10072/56240
dc.description.abstractEndoplasmic 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.
dc.description.peerreviewedYes
dc.description.publicationstatusYes
dc.format.extent3346862 bytes
dc.format.mimetypeapplication/pdf
dc.languageEnglish
dc.publisherRockefeller University Press
dc.publisher.placeUnited States
dc.relation.ispartofstudentpublicationY
dc.relation.ispartofpagefrom1201
dc.relation.ispartofpageto1216
dc.relation.ispartofissue6
dc.relation.ispartofjournalThe Journal of Experimental Medicine
dc.relation.ispartofvolume210
dc.rights.retentionY
dc.subject.fieldofresearchMedical and Health Sciences
dc.subject.fieldofresearchcode11
dc.titleGlucocorticoids alleviate intestinal ER stress by enhancing protein folding and degradation of misfolded proteins
dc.typeJournal article
dc.type.descriptionC1 - Articles
dc.type.codeC - Journal Articles
gro.facultyGriffith Sciences, Griffith Institute for Drug Discovery
gro.rights.copyright© 2013 Rockefeller University Press. The attached file is reproduced here in accordance with the copyright policy of the publisher. Please refer to the journal's website for access to the definitive, published version.
gro.date.issued2013
gro.hasfulltextFull Text
gro.griffith.authorCrane, Denis I.
gro.griffith.authorDas, Indrajit


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