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

ABSTRACT: 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 activa

SUBMITTER: Dr. Eva Cloots 

PROVIDER: S-SCDT-10_1038-S44318-023-00015-Y | biostudies-other |

REPOSITORIES: biostudies-other