title: AGR2 is induced in asthma and promotes allergen-induced mucin overproduction.
abstract: Mucins are gel-forming proteins that are responsible for the characteristic viscoelastic properties of mucus. Mucin overproduction is a hallmark of asthma, but the cellular requirements for airway mucin production are poorly understood. The endoplasmic reticulum (ER) protein anterior gradient homolog 2 (AGR2) is required for production of the intestinal mucin MUC2, but its role in the production of the airway mucins MUC5AC and MUC5B is not established. Microarray data were analyzed to examine the relationship between AGR2 and MUC5AC expression in asthma. Immunofluorescence was used to localize AGR2 in airway cells. Coimmunoprecipitation was used to identify AGR2-immature MUC5AC complexes. Agr2(-/-) mice were used to determine the role of AGR2 in allergic airway disease. AGR2 localized to the ER of MUC5AC- and MUC5B-producing airway cells and formed a complex with immature MUC5AC. AGR2 expression increased together with MUC5AC expression in airway epithelium from "Th2-high" asthmatics. Allergen-challenged Agr2(-/-) mice had greater than 50% reductions in MUC5AC and MUC5B proteins compared with allergen-challenged wild-type mice. Impaired mucin production in Agr2(-/-) mice was accompanied by an increase in the proportion of mucins contained within the ER and by evidence of ER stress in airway epithelium. This study shows that AGR2 increases with mucin overproduction in individuals with asthma and in mouse models of allergic airway disease. AGR2 interacts with immature mucin in the ER and loss of AGR2 impairs allergen-induced MUC5AC and MUC5B overproduction.
authors.affiliation: Lung Biology Center, Department of Medicine, University of California San Francisco, USA.
authors.forename: Bradley W
authors.initials: BW
authors.lastname: Schroeder
authors.forename: Catherine
authors.initials: C
authors.lastname: Verhaeghe
authors.forename: Sung-Woo
authors.initials: SW
authors.lastname: Park
authors.forename: Louis T
authors.initials: LT
authors.lastname: Nguyenvu
authors.forename: Xiaozhu
authors.initials: X
authors.lastname: Huang
authors.forename: Guohua
authors.initials: G
authors.lastname: Zhen
authors.forename: David J
authors.initials: DJ
authors.lastname: Erle
mesh_terms: D000485:Allergens / Q000008:administration & dosage* / Q000276:immunology; D000818:Animals; D001249:Asthma / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D016535:Bronchial Hyperreactivity / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D045744:Cell Line, Tumor; D004721:Endoplasmic Reticulum / Q000276:immunology / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D006969:Hypersensitivity, Immediate / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D055271:Mucin 5AC / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D055257:Mucin-5B / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D009088:Mucoproteins / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015513:Oncogene Proteins; D011506:Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D020545:Respiratory Mucosa / Q000276:immunology / Q000378:metabolism; D018418:Th2 Cells / Q000276:immunology / Q000378:metabolism
chemical_list: C502296:AGR2 protein, human; C526445:Agr2 protein, mouse; D000485:Allergens; D055271:Mucin 5AC; D055257:Mucin-5B; D009088:Mucoproteins; D015513:Oncogene Proteins; D011506:Proteins