Figure 4. UPR signalling in intestinal epithelial cells.

a | Intestinal epithelial cells, particularly Paneth cells, have a well-developed endoplasmic reticulum (ER) to manage their high secretory demands, including the production of antimicrobial proteins such as lysozyme and defensins. b | Deletion of X-box binding protein 1 (XBP1) in the small intestinal epithelium (Xbp1^ΔIEC mice) induces ER stress, resulting in hypomorphic Paneth cells that have signs of inositol-requiring enzyme 1α (IRE1α) hyperactivation and downstream activation of nuclear factor-κB (NF-κB) and JUN N-terminal kinase (JNK). The induction of autophagy through the PKR-like ER kinase (PERK)-eukaryotic translation initiation factor 2α (eIF2α)-activating transcription factor 4 (ATF4) axis of the unfolded protein response (UPR) alleviates ER stress. c | Simultaneous deletion of XBP1 and autophagy-related 16 like 1 (ATG16L1) in the small intestinal epithelium thus further increases ER stress and ER stress-induced inflammation. Hypothetically, ER stress, which induces caspase 3, could be an important pathway responsible for the degradation of ATG16L1 in patients carrying the Crohn’s disease risk allele ATG16L1^T300A, which is prone to caspase 3-mediated cleavage.