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The IRE1β-mediated unfolded protein response is repressed by the chaperone AGR2 in mucin producing cells

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Effector mechanisms in the Endoplasmic Reticulum (ER) Unfolded Protein Response (UPR) are well characterised but sensing ER proteostasis is less well understood. Here we exploited a mucin producing cell-specific isoform of the UPR transducer IRE1β to gauge the relative regulatory role of activating ligands and repressing chaperones of the specialised ER of goblet cells. Replacement of the stress-sensing luminal domain (LD) of endogenous IRE1α in CHO cells (normally expressing neither mucin nor IRE1β) by the IRE1β LD deregulated basal IRE1 activity. The mucin-specific chaperone AGR2 repressed IRE1 activity in cells expressing the domain swapped IRE1β/α chimera but had no effect on IRE1α. Introduction of the goblet-cell specific client MUC2, reversed the AGR2 mediated repression of the IRE1β/α chimera. In vitro, AGR2 actively de-stabilised the IRE1β-LD dimer and formed a reversible complex with the inactive monomer. These features of the IRE1β-AGR2 couple suggest that active repression of IRE1β by a specialised mucin chaperone subordinates IRE1 activity to a proteostatic challenge unique to goblet cells, a challenge that is otherwise poorly recognised by the pervasive UPR transducers.


Funder: Medical Research Council DTP and Gates Cambridge PhD programme

Funder: Erasmus+


Molecular Chaperones, Unfolded Protein Response (UPR), Endoplasmic Reticulum (ER), Mucin, Protein Multimerisation, Animals, Cricetinae, Humans, Cricetulus, Endoribonucleases, Goblet Cells, Molecular Chaperones, Mucins, Mucoproteins, Oncogene Proteins, Protein Serine-Threonine Kinases, CHO Cells

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EMBO Journal

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EMBO Press
Medical Research Council (2304568)
Wellcome Trust (224407/Z/21/Z)