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.