title: The ER stress transducer IRE1β is required for airway epithelial mucin production.
abstract: Inflammation of human bronchial epithelia (HBE) activates the endoplasmic reticulum (ER) stress transducer inositol-requiring enzyme 1 (IRE1)α, resulting in IRE1α-mediated cytokine production. Previous studies demonstrated ubiquitous expression of IRE1α and gut-restricted expression of IRE1β. We found that IRE1β is also expressed in HBE, is absent in human alveolar cells, and is upregulated in cystic fibrosis and asthmatic HBE. Studies with Ire1β(-/-) mice and Calu-3 airway epithelia exhibiting IRE1β knockdown or overexpression revealed that IRE1β is expressed in airway mucous cells, is functionally required for airway mucin production, and this function is specific for IRE1β vs. IRE1α. IRE1β-dependent mucin production is mediated, at least in part, by activation of the transcription factor X-box binding protein-1 (XBP-1) and the resulting XBP-1-dependent transcription of anterior gradient homolog 2, a gene implicated in airway and intestinal epithelial mucin production. These novel findings suggest that IRE1β is a potential mucous cell-specific therapeutic target for airway diseases characterized by mucin overproduction.
authors.affiliation: Cystic Fibrosis/Pulmonary Research and Treatment Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: M B
authors.initials: MB
authors.lastname: Martino
authors.forename: L
authors.initials: L
authors.lastname: Jones
authors.forename: B
authors.initials: B
authors.lastname: Brighton
authors.forename: C
authors.initials: C
authors.lastname: Ehre
authors.forename: L
authors.initials: L
authors.lastname: Abdulah
authors.forename: C W
authors.initials: CW
authors.lastname: Davis
authors.forename: D
authors.initials: D
authors.lastname: Ron
authors.forename: W K
authors.initials: WK
authors.lastname: O'Neal
authors.forename: C M P
authors.initials: CM
authors.lastname: Ribeiro
mesh_terms: D000818:Animals; D001249:Asthma / Q000235:genetics / Q000276:immunology*; D002460:Cell Line; D003550:Cystic Fibrosis / Q000235:genetics / Q000276:immunology*; D004268:DNA-Binding Proteins / Q000378:metabolism; D004722:Endoribonucleases / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009077:Mucins / Q000378:metabolism; D020033:Protein Isoforms / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D000071701:Regulatory Factor X Transcription Factors; D020545:Respiratory Mucosa / Q000276:immunology*; D014157:Transcription Factors / Q000378:metabolism; D019076:Transgenes / Q000235:genetics; D015854:Up-Regulation; D000071717:X-Box Binding Protein 1
chemical_list: D004268:DNA-Binding Proteins; D008565:Membrane Proteins; D009077:Mucins; D020033:Protein Isoforms; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1; C000605543:XBP1 protein, human; C000605544:Xbp1 protein, mouse; C486556:Ern2 protein, mouse; C510185:Ern1 protein, mouse; D017346:Protein Serine-Threonine Kinases; D004722:Endoribonucleases