The intestinal mucus barrier forms an essential line of defense against pathogens, but how this barrier is regulated remains poorly understood. Both defects in mucus production and protein folding quality control (i.e. the unfolded protein response (UPR)) are risk factors for inflammatory bowel disease (IBD). This is not surprising, as a steep rise in protein production (such as the increase in mucin glycoproteins during inflammation) generally requires the UPR program to protect cellular homeostasis. While some insights have been gained into the role of the ubiquitous UPR sensor IRE1α in the intestine, mucus producing goblet cells express a second IRE1 isoform, IRE1β, at 50-fold higher expression levels than IRE1α. To date the role of IRE1β in the mucosal epithelial niche is largely unknown, partly because ectopic IRE1β expression results in cell death. This hampered research into IRE1β, but also caused doubt on its physiological role. I identified the goblet cell specific chaperone AGR2 as a regulator of IRE1β that fully prevents from IRE1β-mediated toxicity. Removal of either AGR2 or IRE1β in mice leads to susceptibility to colitis, indicating that both proteins are important in intestinal homeostasis. In this project I aim to elucidate the biochemical properties and in vivo importance of the AGR2-IRE1β complex. As defects in either the UPR and mucus production are linked to IBD and colitis, understanding how both processes are intertwined is highly clinically relevant.