ArticleThe EMBO journal2024
Activation of goblet-cell stress sensor IRE1β is controlled by the mucin chaperone AGR2.
Article in The EMBO journal, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed, 28 citations in OpenAlex.
- Cadherin 1 negatively regulates SARS-CoV-2 infection in the olfactory epithelium.EMBO reports · 2026Article
- The unfolded protein sensor IRE1 is essential for homeostatic dendritic cell maturation.Nature communications · 2026Article
- A regulatory circuit operated by KDELR1 and KDELR3 fine-tunes the composition of the early secretory pathway.Cellular and molecular life sciences : CMLS · 2026Article
- Airway mucus in infection.Frontiers in physiology · 2026Review
- Mucin 2 and unfolded protein response reshape the mucus barrier in inflammatory bowel disease (Review).Molecular medicine reports · 2026Review
- Article
- Non-Canonical, Strongly Selective Protein Disulfide Isomerases as Anticancer Therapeutic Targets.Biomolecules · 2025Review
- DR5 Disulfide Bonding Functions as a Sensor and Effector of Protein Folding Stress.Molecular cancer research : MCR · 2025Article
- Disrupting AGR2/IGF1 paracrine and reciprocal signaling for pancreatic cancer therapy.Cell reports. Medicine · 2025Article
- Progressive lung fibrosis: reprogramming a genetically vulnerable bronchoalveolar epithelium.The Journal of clinical investigation · 2025Review
- Utilizing Corneal Fluorescein and Conjunctival Lissamine Green Staining Combined with in vivo Confocal Microscopy for Grading the Severity of Dry Eye Disease.Clinical ophthalmology (Auckland, N.Z.) · 2025Article
- TMX5/TXNDC15, a natural trapping mutant of the PDI family is a client of the proteostatic factor ERp44.Life science alliance · 2024Article
- Review
- Essential roles of the unfolded protein response in intestinal physiology.eGastroenterology · 2024Review
- AGR2: The Covert Driver and New Dawn of Hepatobiliary and Pancreatic Cancer Treatment.Biomolecules · 2024Review
- Exploring the IRE1 interactome: From canonical signaling functions to unexpected roles.The Journal of biological chemistry · 2024Review
- The IRE1β-mediated unfolded protein response is repressed by the chaperone AGR2 in mucin producing cells.The EMBO journal · 2024Article
- Cigarette Smoke Extract Induces MUC5AC Expression Through the ROS/ IP3R/CaInternational journal of chronic obstructive pulmonary disease · 2024Article
Corrections and comments
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Authors and funding
10 authors at 4 institutions in 2 countries.
Funding
Abstract
Intestinal goblet cells are secretory cells specialized in the production of mucins, and as such are challenged by the need for efficient protein folding. Goblet cells express Inositol-Requiring Enzyme-1β (IRE1β), a unique sensor in the unfolded protein response (UPR), which is part of an adaptive mechanism that regulates the demands of mucin production and secretion. However, how IRE1β activity is tuned to mucus folding load remains unknown. We identified the disulfide isomerase and mucin chaperone AGR2 as a goblet cell-specific protein that crucially regulates IRE1β-, but not IRE1α-mediated signaling. AGR2 binding to IRE1β disrupts IRE1β oligomerization, thereby blocking its downstream endonuclease activity. Depletion of endogenous AGR2 from goblet cells induces spontaneous IRE1β activation, suggesting that alterations in AGR2 availability in the endoplasmic reticulum set the threshold for IRE1β activation. We found that AGR2 mutants lacking their catalytic cysteine, or displaying the disease-associated mutation H117Y, were no longer able to dampen IRE1β activity. Collectively, these results demonstrate that AGR2 is a central chaperone regulating the goblet cell UPR by acting as a rheostat of IRE1β endonuclease activity.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.