Anterior gradient 2 (AGR2) is a dimeric protein disulfide isomerase family member involved in the regulation of protein quality control in the endoplasmic reticulum (ER). Mouse AGR2 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 AGR2 function toward inflammation remain poorly defined. Here, using a protein-protein interaction screen to identify cellular regulators of AGR2 dimerization, we unveiled specific enhancers, including TMED2, and inhibitors of AGR2 dimerization, that control AGR2 functions. We demonstrate that modulation of AGR2 dimer formation, whether enhancing or inhibiting the process, yields pro-inflammatory phenotypes, through either autophagy-dependent processes or secretion of AGR2, respectively. We also demonstrate that in IBD and specifically in Crohn's disease, the levels of AGR2 dimerization modulators are selectively deregulated, and this correlates with severity of disease. Our study demonstrates that AGR2 dimers act as sensors of ER homeostasis which are disrupted upon ER stress and promote the secretion of AGR2 monomers. The latter might represent systemic alarm signals for pro-inflammatory responses.

APHP Beaujon Hospital Clichy la Garenne Paris France

Apoptosis Research Centre School of Natural Sciences NUI Galway Galway Ireland

Biochemistry Department McGill University Life Sciences Complex Montréal QC Canada

Centre de Lutte Contre le Cancer Eugène Marquis Rennes France

Department of Chemistry and Molecular Biology University of Gothenburg Göteborg Sweden

Departments of Anatomy and Cell Biology Human Genetics and Pediatrics McGill University Montreal QC Canada

Division of Oncology Research Department of Oncology Schulze Center for Novel Therapeutics Mayo Clinic Rochester MN USA

e NIOS PC Kallithea Athens Greece

Edinburgh Cancer Research Centre at the Institute of Genetics and Molecular Medicine Edinburgh University Edimburgh UK

INSERM U1242 Chemistry Oncogenesis Stress Signaling University of Rennes Rennes France

INSERM UMR1149 Team «Gut Inflammation» Research Centre of Inflammation Paris France

Institute of Biology Medicinal Chemistry and Biotechnology NHRF Athens Greece

International Centre for Cancer Vaccine Science Gdansk Poland

Microscopy Rennes Imaging Centre and Biosit UMS3480 CNRS University of Rennes 1 Rennes Cédex France

Regional Centre for Applied Molecular Oncology Brno Czech Republic

Université Paris Diderot Sorbonne Paris Cité Paris France

University of Bordeaux Bordeaux France

VIB Department of Medical Protein Research UGent Gent Belgium

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