High MUC2 Mucin Expression and Misfolding Induce Cellular Stress, Reactive Oxygen Production, and Apoptosis in Goblet Cells

MUC2 mucin is a large glycoprotein produced by goblet cells that forms the protective mucus blanket overlying the intestinal epithelium as the first line of innate host defense. High MUC2 production in inflammatory bowel disease and infectious colitis depletes goblet cells and the mucus layer by an unknown mechanism. Herein, we analyzed the effect of high MUC2 biosynthesis on endoplasmic reticulum (ER) stress and apoptosis in goblet cells using a high MUC2-producing human goblet cell line (HT29-H) and an HT29-H clone (HT29-L) silenced for MUC2 expression by lentivirus-mediated shRNA. Goblet cell ER stress and apoptosis were quantified during early onset of dextran sulfate sodiuminduced colitis in C57BL/6 and Mathl(M1GFP) mice. Compared with HT29-L and MUC2 nonproducing Caco-2 cells, high MUC2-producing HT29-H cells had significantly increased ER stress and apoptosis after treatment with ER stress-inducing agents. Apoptosis was driven by increased misfolded MUC2 that triggered elevated levels of reactive oxygen species. Correcting MUC2 folding and inhibiting reactive oxygen species alleviated ER stress and rescued cells from apoptosis. During early-onset colitis, mucus hypersecretion caused severe ER stress and apoptosis of goblet cells that preceded absorptive epithelial cell damage. Thus, in gastrointestinal inflammation, high MUC2 biosynthesis and goblet cell apoptosis lead to a dysfunctional epithelial barrier. Enhancing MUC2 folding may help alleviate goblet cell depletion and maintain mucosal integrity.