Negative feedback by IRE1β optimizes mucin production in goblet cells

In mammals, the prototypical endoplasmic reticulum (ER) stress sensor inositol-requiring enzyme 1 (IRE1) has diverged into two paralogs. IRE1 alpha is broadly expressed and mediates the unconventional splicing of X-box binding protein 1 (XBP1) mRNA during ER stress. By contrast, IRE1 beta is expressed selectively in the digestive tract, and its function remains unclear. Here, we report that IRE1 beta plays a distinctive role in mucin-secreting goblet cells. In IRE1 beta(-/-) mice, aberrant mucin 2 (MUC2) accumulated in the ER of goblet cells, accompanied by ER distension and elevated ER stress signaling such as increased XBP1 mRNA splicing. In contrast, conditional IRE1 alpha(-/-) mice showed no such ER distension but a marked decrease in spliced XBP1 mRNA. mRNA stability assay revealed that MUC2 mRNA was greatly stabilized in IRE1 beta(-/-) mice. These findings suggest that in goblet cells, IRE1 beta, but not IRE1 alpha, promotes efficient protein folding and secretion in the ER by optimizing the level of mRNA encoding their major secretory product, MUC2.