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dc.contributor.authorDas, Indrajiten_US
dc.contributor.authorPng, Chin Wenen_US
dc.contributor.authorOancea, Iuliaen_US
dc.contributor.authorZ. Hasnain, Sumairaen_US
dc.contributor.authorLourie, Rohanen_US
dc.contributor.authorProctor, Martinaen_US
dc.contributor.authorD. Eri, Rajaramanen_US
dc.contributor.authorSheng, Yongen_US
dc.contributor.authorCrane, Denisen_US
dc.contributor.authorH. Florin, Timothyen_US
dc.contributor.authorA. McGuckin, Michaelen_US
dc.date.accessioned2017-05-03T11:02:03Z
dc.date.available2017-05-03T11:02:03Z
dc.date.issued2013en_US
dc.date.modified2014-01-30T22:25:43Z
dc.identifier.issn00221007en_US
dc.identifier.doi10.1084/jem.20121268en_US
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.en_US
dc.description.peerreviewedYesen_US
dc.description.publicationstatusYesen_US
dc.format.extent3346862 bytes
dc.format.mimetypeapplication/pdf
dc.languageEnglishen_US
dc.publisherRockefeller University Pressen_US
dc.publisher.placeUnited Statesen_US
dc.relation.ispartofstudentpublicationYen_US
dc.relation.ispartofpagefrom1201en_US
dc.relation.ispartofpageto1216en_US
dc.relation.ispartofissue6en_US
dc.relation.ispartofjournalThe Journal of Experimental Medicineen_US
dc.relation.ispartofvolume210en_US
dc.rights.retentionYen_US
dc.subject.fieldofresearchcode270199en_US
dc.titleGlucocorticoids alleviate intestinal ER stress by enhancing protein folding and degradation of misfolded proteinsen_US
dc.typeJournal articleen_US
dc.type.descriptionC1 - Peer Reviewed (HERDC)en_US
dc.type.codeC - Journal Articlesen_US
gro.facultyGriffith Sciences, Griffith Institute for Drug Discoveryen_US
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.en_US
gro.date.issued2013
gro.hasfulltextFull Text


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