Activation of goblet cell stress sensor IRE1β is controlled by the mucin chaperone AGR2

Cloots, E.; Guilbert, P.; Provost, M.; Neidhardt, L.; Van de Velde, E.; Fayazpour, F.; De Sutter, D.; Savvides, S. N.; Eyckerman, S.; Janssens, S.

doi:10.1101/2023.07.06.547951

bioRxiv · 10.1101/2023.07.06.547951

Activation of goblet cell stress sensor IRE1β is controlled by the mucin chaperone AGR2

Cloots, E.·Guilbert, P.·Provost, M.·Neidhardt, L.·Van de Velde, E.·Fayazpour, F.·De Sutter, D.·Savvides, S. N.·Eyckerman, S.·Janssens, S.

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Abstract

As secretory cells specialized in the production of mucins, intestinal goblet cells are challenged by the need for efficient protein folding. Goblet cells express Inositol-Requiring Enzyme 1{beta} (IRE1{beta}), a unique unfolded protein response (UPR) sensor that is part of an adaptive mechanism that regulates the demands of mucin production and secretion. However, how IRE1{beta} 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 IRE1{beta}-, but not IRE1-mediated signaling. AGR2 binding to IRE1{beta} disrupts IRE1{beta} dimerization, thereby blocking its downstream endonuclease activity. Depletion of endogenous AGR2 from goblet cells induces spontaneous IRE1{beta} activation, suggesting that alterations in AGR2 availability in the endoplasmic reticulum sets the threshold for IRE1{beta} activation. We found that AGR2 mutants lacking their catalytic cysteine or displaying the disease-associated mutation H117Y were no longer able to dampen IRE1{beta} activity. Collectively, these results demonstrate that AGR2 is a central chaperone regulating the goblet cell UPR by acting as a rheostat of IRE1{beta} endonuclease activity.

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Cloots, E., Guilbert, P., Provost, M., Neidhardt, L., Van de Velde, E., Fayazpour, F., De Sutter, D., Savvides, S. N., Eyckerman, S., Janssens, S.. 2023-07-07. Activation of goblet cell stress sensor IRE1β is controlled by the mucin chaperone AGR2. https://doi.org/10.1101/2023.07.06.547951

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