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

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Van de Velde, Evelien 


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.


Acknowledgements: SJ, SE, and SNS are supported by the Vlaams Instituut voor Biotechnologie (VIB). This research was further supported by Fonds Wetenschappelijk Onderzoek (FWO) (1228923N to EC, G017521N to SJ, and G049820N, G0H1222N, S000722N, S002322N to SNS), an ERC Consolidator grant (DCRIDDLE- 819314 to SJ) and the Geconcerteerde Onderzoeksacties, Special Research fund, Ghent University (BOF16/GOA/023 to SE). LN is supported by Medical Research Council DTP and Gates Cambridge PhD programme. We would like to thank the VIB Proteomics core, the VIB Flow core and the VIB-IRC Tissue Culture Core for training, support and access to the instrument park and facility. We thank David Ron for feedback on the manuscript, and for providing IRE1β antiserum. We would like to thank Michael J Grey for constructive discussions and advice.

Funder: Medical Research Council DTP and Gates Cambridge PhD Programme


AGR2, Goblet Cells, IRE1β, Mucus Homeostasis, Unfolded Protein Response (UPR), Endonucleases, Goblet Cells, Molecular Chaperones, Mucins, Protein Disulfide-Isomerases, Humans, Cell Line, Tumor

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Springer Science and Business Media LLC
Fonds Wetenschappelijk Onderzoek (FWO) (1228923N, G017521N, G049820N,G0H1222N,S000722N,S002322N)
EC | ERC | HORIZON EUROPE European Research Council (ERC) (DCRIDDLE- 819314)
UGent | Bijzonder Onderzoeksfonds UGent (BOF) (BOF16/GOA/023)