Negative feedback by IRE1β optimizes mucin production in goblet cells

Abstract

In mammals, the prototypical endoplasmic reticulum (ER) stress sensor inositol-requiring enzyme 1 (IRE1) has diverged into two paralogs. IRE1α is broadly expressed and mediates the unconventional splicing of X-box binding protein 1 (XBP1) mRNA during ER stress. By contrast, IRE1β is expressed selectively in the digestive tract, and its function remains unclear. Here, we report that IRE1β plays a distinctive role in mucin-secreting goblet cells. In IRE1β −/− 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 IRE1α −/− 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 IRE1β −/− mice. These findings suggest that in goblet cells, IRE1β, but not IRE1α, promotes efficient protein folding and secretion in the ER by optimizing the level of mRNA encoding their major secretory product, MUC2.inflammatory bowel disease | unfolded protein response

Innate immunity at mucosal surfaces: the IRE1-RIDD-RIG-I pathway

“…Genetic deletion of IRE1β in mice predisposes the intestine to severe forms of chemically induced colitis, indicating a role for IRE1β in mucosal inflammation [65]. Strong evidence implicates IRE1β in the regulation of production of mucin – a component of the mucosal barrier [65] – by intestinal goblet cells [72,73]. The RIDD activity of IRE1β is considered essential for maintaining normal goblet cell function in the intestine by preventing ER stress [73].…”

“…Strong evidence implicates IRE1β in the regulation of production of mucin – a component of the mucosal barrier [65] – by intestinal goblet cells [72,73]. The RIDD activity of IRE1β is considered essential for maintaining normal goblet cell function in the intestine by preventing ER stress [73]. In the lung, however, regulation of mucin secretion by IRE1β depends on XBP-1.…”

The Endoplasmic Reticulum Stress Sensor IRE1α in Intestinal Epithelial Cells Is Essential for Protecting against Colitis

“…Genetic deletion of Xbp1 in IECs caused spontaneous enteritis in mice (19), whereas deletion of IRE1␤ led to higher susceptibility to dextran sulfate sodium (DSS)-induced colitis (11). Further studies show that IRE1␤ optimizes the production of mucin in goblet cells, indicating that IRE1␤ is involved in ER homeostasis in goblet cells (21). It still remains elusive whether or not IRE1␣ is involved in the homeostatic control of the intestinal epithelium.…”

Mucins and Mucus

“…Photomicrographs of murine cecum stained with Alcian blue to identify stored mucins in the goblet cells. Courtesy of Dr Sumaira Zia Hasnain. results in misfolding of Muc2 in the basal goblet cell lineage (Tsuru et al, 2013).…”