Control of anterior GRadient 2 (AGR2) dimerization links endoplasmic reticulum proteostasis to inflammation
Marion Maurel , Joanna Obacz , Tony Avril , Yong‐Ping Ding , Olga Papadodima , Xavier Treton , Fanny Daniel , Eleftherios Pilalis , Johanna Hörberg , Wenyang Hou , Marie‐Claude Beauchamp , Julien Tourneur‐Marsille , Dominique Cazals‐Hatem , Lucia Sommerova , Afshin Samali , Jan Tavernier , Roman Hrstka , Aurélien Dupont , Delphine Fessart , Frédéric Delom , Martin E Fernandez‐Zapico , Gregor Jansen , Leif A Eriksson , David Y Thomas , Loydie Jerome‐Majewska , Ted Hupp , Aristotelis Chatziioannou , Eric Chevet , Eric Ogier‐Denis
AbstractAnterior 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.
|Journal series||EMBO Molecular Medicine, ISSN 1757-4676, (N/A 200 pkt)|
|Publication size in sheets||0.90|
|Keywords in English||AGR2, endoplasmic reticulum, inflammation, proteostasis, TMED2|
|License||Journal (articles only); published final; ; with publication|
|Score||= 200.0, 30-01-2020, ArticleFromJournal|
|Publication indicators||: 2018 = 1.954; : 2018 = 10.624 (2) - 2018=10.382 (5)|
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