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 inositolrequiring 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.

Barrier Epithelial Cells and the Control of Type 2 Immunity

“…One possibility is that secretion of mucins interferes with the unfolded protein response ([UPR], a cellular response to stress), that can intersect with inflammatory response pathways, including NF-kB activation (Janssens et al, 2014). In airway epithelial cells of human asthmatics, IL-13-induced GCM leads to induction of Xbp1 splicing (Martino et al, 2013). This process is very similar to mucus production in the gut and depends on the mucosalrestricted endoplasmic reticulum (ER) stress sensor IRE1b, leading to induction of the protein disulfide isomerase Agr2.…”

Oxidative and endoplasmic reticulum stress in respiratory disease

“…Expression and production of mucins can also be upregulated by inflammatory cytokines including IL‐1β,27 IL‐4,28 IL‐6,29 IL‐9,30 IL‐13,31 TNF‐α,32 nitric oxide,33 neutrophil elastase34 and other uncharacterised inflammatory factors, which might contribute to pathogenesis in human inflammatory airway disorders. IRE1β can also regulate mucin production, linking the UPR to mucin expression 35. However, if the increased production of mucin proteins is not resolved, mucus accumulation may contribute to the pathogenesis of human inflammatory airway disorders.…”

Inhibition of soluble epoxide hydrolase attenuates hepatic fibrosis and endoplasmic reticulum stress induced by carbon tetrachloride in mice

“…The unfolded protein response consists of three major branches that are controlled by the ER transmembrane proteins PKR-like ER-regulated kinase (PERK), inositol requiring protein 1α (IRE1α), and activating transcription factor 6 (ATF6) (Hotamisligil; Hummasti and Hotamisligil; Ron and Walter, 2007). In particular, the IRE1α sub-arm of ER stress signaling is critical for the unfolded protein response in fibrotic tissues (Chiang et al , 2011; Martino et al , 2013). The various unfolded protein response sub-arms synergize to attenuate stress by increasing the folding capacity of the ER (Schroder and Kaufman, 2005).…”