Control of anterior GR adient 2 ( AGR 2) dimerization links endoplasmic reticulum proteostasis to inflammation

Anterior gradient 2 ( AGR 2) is a dimeric protein disulfide isomerase family member involved in the regulation of protein quality control in the endoplasmic reticulum ( ER ). Mouse AGR 2 deletion increases intestinal inflammation and promotes the development of inflammatory bowel disease ( IBD ). Although these biological effects are well established, the underlying molecular mechanisms of AGR 2 function toward inflammation remain poorly defined. Here, using a protein–protein interaction screen to identify cellular regulators of AGR 2 dimerization, we unveiled specific enhancers, including TMED 2, and inhibitors of AGR 2 dimerization, that control AGR 2 functions. We demonstrate that modulation of AGR 2 dimer formation, whether enhancing or inhibiting the process, yields pro‐inflammatory phenotypes, through either autophagy‐dependent processes or secretion of AGR 2, respectively. We also demonstrate that in IBD and specifically in Crohn's disease, the levels of AGR 2 dimerization modulators are selectively deregulated, and this correlates with severity of disease. Our study demonstrates that AGR 2 dimers act as sensors of ER homeostasis which are disrupted upon ER stress and promote the secretion of AGR 2 monomers. The latter might represent systemic alarm signals for pro‐inflammatory responses.