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

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. Synopsis: IRE1β is specifically expressed in mucin-secreting goblet cells of the mammalian gut. Here, the mucin chaperone AGR2 is identified as master regulator of IRE1β oligomerization and endonuclease activity. The protein disulfide isomerase AGR2 acts as a specific interactor of the unfolded protein response sensor IRE1β in colon epithelial cells. AGR2 inhibits IRE1β endonuclease activity by promoting IRE1β monomerization. The inflammatory bowel disease-associated AGR2^H117Y mutant loses its repressive activity on IRE1β. AGR2 regulates IRE1β UPR sensor activity by holding it in a monomeric inactive state. [ABSTRACT FROM AUTHOR]