The ER stress transducer IRE1β is required for airway epithelial mucin production

Inflammation of human bronchial epithelia (HBE) activates the endoplasmic reticulum (ER) stress transducer inositol-requiring enzyme 1 (IRE1)alpha, resulting in IRE1 alpha-mediated cytokine production. Previous studies demonstrated ubiquitous expression of IRE1 alpha and gut-restricted expression of IRE1 beta. We found that IRE1 beta is also expressed in HBE, is absent in human alveolar cells, and is upregulated in cystic fibrosis and asthmatic HBE. Studies with Ire1 beta(-/-) mice and Calu-3 airway epithelia exhibiting IRE1 beta knockdown or overexpression revealed that IRE1 beta is expressed in airway mucous cells, is functionally required for airway mucin production, and this function is specific for IRE1 beta vs. IRE1 alpha. IRE1 beta-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 IRE1 beta is a potential mucous cell-specific therapeutic target for airway diseases characterized by mucin overproduction.