Mucin 2 and unfolded protein response reshape the mucus barrier in inflammatory bowel disease (Review).

Mucin 2 (MUC2) is the primary structural component of the intestinal mucus layer and is essential for maintaining the integrity of the mucus barrier and influencing the development of inflammatory bowel disease (IBD). Disruption of MUC2 production or secretion compromises barrier function, increasing susceptibility to the chronic mucosal inflammation characteristic of IBD. Given their large size and complex folding requirements, immature MUC2 precursors easily accumulate in the endoplasmic reticulum (ER) and cause ER stress, leading to activation of the unfolded protein response (UPR). The UPR restores ER homeostasis by reducing protein synthesis, enhancing folding, and degrading misfolded proteins. The mammalian UPR has three known signaling branches: Pancreatic ER kinase, ER transmembrane inositol‑requiring enzymes 1α and β (IRE1α and IRE1β) and activating transcription factor 6. Anterior gradient 2 (AGR2) is a dimeric protein disulfide isomerase family member involved in the regulation of protein quality control in the ER. Importantly, IRE1β‑AGR2 signaling potentially serves as a superior regulatory mechanism for controlling UPR activation caused by the misfolding of MUC2 in goblet cells. The present review highlights the critical role of MUC2 dysfunction and UPR imbalance in IBD pathogenesis. Targeting the association between novel UPR signaling pathways and restoring MUC2 protein function may provide new insights into IBD research and treatment.