The intestinal mucus barrier is an essential component of the host defense against pathogens, and defects in this barrier are important risk factors for inflammatory bowel disease (IBD). Mucus consists of a large protein core and sugar branches, forming intricate polymers. Infection leads to a steep increase in mucus production, and folding and secretion of these glycoproteins puts a major burden on the secretory organelle of the cell, the endoplasmic reticulum. This triggers an unfolded protein response (UPR) which restores the protein folding balance. For mucus-producing goblet cells this pathway has not been fully characterized. Goblet cells have a unique UPR in the sense that they express a second isoform of the UPR sensor IRE1, called IRE1b. The function of this second isoform has remained elusive as ectopic expression of IRE1b is toxic to most cell lines. We identified the goblet cell specific chaperone AGR2 as a regulator of IRE1b, and AGR2 co-expression inhibits IRE1b hyperactivity. Removal of either protein in mice leads to susceptibility to colitis, indicating that this protein complex is a major player in goblet cell homeostasis. This project aims to elucidate the biochemical properties of this protein complex, as well as its role in mucosal immunology and host defense. From genetic evidence we know that defects in the UPR are linked to IBD and colitis. With this project we aim to understand how both processes are intertwined.