Activation of goblet-cell stress sensor IRE1β is controlled by the mucin chaperone AGR2
- Author
- Eva Cloots (UGent) , Phaedra Guilbert (UGent) , Mathias Provost (UGent) , Lisa Neidhardt, Evelien Van De Velde (UGent) , Farzaneh Fayazpour (UGent) , Delphine De Sutter (UGent) , Savvas Savvides (UGent) , Sven Eyckerman (UGent) and Sophie Janssens (UGent)
- Organization
- Project
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- Molecular mechanism and functional implications of the AGR2-IRE1ß axis in goblet cell homeostasis
- Regulation of goblet cell homeostasis by the AGR2-IRE1b axis
- An integrated approach to unravel eosinophil function in chronic eosinophilic disorders
- Targeting transcription factor addiction in acute leukemia (TaTFAL)
- Rational design of biologics for therapeutic development (FoldCo)
- Long noncoding RNAs in cancer: deciphering the functional role of the dark matter of the human cancer genome
- Towards the structural and molecular basis of pro-inflammatory signalling assemblies mediated by IL-23 and IL-12
- Unraveling the structural and functional roles of THEMIS proteins in T cell and B cell development and inflammation
- 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.
- Keywords
- AGR2, Goblet Cells, IRE1 beta, Mucus Homeostasis, Unfolded Protein Response (UPR), ENDOPLASMIC-RETICULUM STRESS, REGULATED IRE1-DEPENDENT DECAY, UNFOLDED-PROTEIN-RESPONSE, TRANSLATIONAL CONTROL, ER STRESS, MESSENGER-RNAS, MUCUS BARRIER, IRE1, SECRETION, REQUIRES
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Citation
Please use this url to cite or link to this publication: http://hdl.handle.net/1854/LU-01HKCRY5G8EZCZEVMEJPTSG5V9
- MLA
- Cloots, Eva, et al. “Activation of Goblet-Cell Stress Sensor IRE1β Is Controlled by the Mucin Chaperone AGR2.” EMBO JOURNAL, vol. 43, no. 5, 2024, pp. 695–718, doi:10.1038/s44318-023-00015-y.
- APA
- Cloots, E., Guilbert, P., Provost, M., Neidhardt, L., Van De Velde, E., Fayazpour, F., … Janssens, S. (2024). Activation of goblet-cell stress sensor IRE1β is controlled by the mucin chaperone AGR2. EMBO JOURNAL, 43(5), 695–718. https://doi.org/10.1038/s44318-023-00015-y
- Chicago author-date
- Cloots, Eva, Phaedra Guilbert, Mathias Provost, Lisa Neidhardt, Evelien Van De Velde, Farzaneh Fayazpour, Delphine De Sutter, Savvas Savvides, Sven Eyckerman, and Sophie Janssens. 2024. “Activation of Goblet-Cell Stress Sensor IRE1β Is Controlled by the Mucin Chaperone AGR2.” EMBO JOURNAL 43 (5): 695–718. https://doi.org/10.1038/s44318-023-00015-y.
- Chicago author-date (all authors)
- Cloots, Eva, Phaedra Guilbert, Mathias Provost, Lisa Neidhardt, Evelien Van De Velde, Farzaneh Fayazpour, Delphine De Sutter, Savvas Savvides, Sven Eyckerman, and Sophie Janssens. 2024. “Activation of Goblet-Cell Stress Sensor IRE1β Is Controlled by the Mucin Chaperone AGR2.” EMBO JOURNAL 43 (5): 695–718. doi:10.1038/s44318-023-00015-y.
- Vancouver
- 1.Cloots E, Guilbert P, Provost M, Neidhardt L, Van De Velde E, Fayazpour F, et al. Activation of goblet-cell stress sensor IRE1β is controlled by the mucin chaperone AGR2. EMBO JOURNAL. 2024;43(5):695–718.
- IEEE
- [1]E. Cloots et al., “Activation of goblet-cell stress sensor IRE1β is controlled by the mucin chaperone AGR2,” EMBO JOURNAL, vol. 43, no. 5, pp. 695–718, 2024.
@article{01HKCRY5G8EZCZEVMEJPTSG5V9,
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.}},
author = {{Cloots, Eva and Guilbert, Phaedra and Provost, Mathias and Neidhardt, Lisa and Van De Velde, Evelien and Fayazpour, Farzaneh and De Sutter, Delphine and Savvides, Savvas and Eyckerman, Sven and Janssens, Sophie}},
issn = {{0261-4189}},
journal = {{EMBO JOURNAL}},
keywords = {{AGR2,Goblet Cells,IRE1 beta,Mucus Homeostasis,Unfolded Protein Response (UPR),ENDOPLASMIC-RETICULUM STRESS,REGULATED IRE1-DEPENDENT DECAY,UNFOLDED-PROTEIN-RESPONSE,TRANSLATIONAL CONTROL,ER STRESS,MESSENGER-RNAS,MUCUS BARRIER,IRE1,SECRETION,REQUIRES}},
language = {{eng}},
number = {{5}},
pages = {{695--718}},
title = {{Activation of goblet-cell stress sensor IRE1β is controlled by the mucin chaperone AGR2}},
url = {{http://doi.org/10.1038/s44318-023-00015-y}},
volume = {{43}},
year = {{2024}},
}
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