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These authors contributed equally to this work

This study provides molecular insights into the anterior gradient 2 (AGR2) mode of action in the endoplasmic reticulum (ER) with an emphasis on the regulation of AGR2 dimers. Dysregulation of AGR2 dimer formation leads to inflammation as seen in inflammatory bowel disease (IBD) and Crohn's disease.

This study provides molecular insights into the anterior gradient 2 (AGR2) mode of action in the endoplasmic reticulum (ER) with an emphasis on the regulation of AGR2 dimers. Dysregulation of AGR2 dimer formation leads to inflammation as seen in inflammatory bowel disease (IBD) and Crohn's disease.

AGR2 is a chaperone involved in the regulation of protein quality control in the ER. We have developed and used a novel cellular proteinprotein interaction screen to identify cellular regulators of AGR2 dimerization.

We identify specific enhancers, including TMED2, and inhibitors of AGR2 dimerization, that control AGR2 functions.

Modulation of AGR2 dimer formation, whether enhancing or inhibiting the process, yields proinflammatory phenotypes, through either autophagydependent processes or secretion of AGR2, respectively.

In IBD and specifically in Crohn's disease, the levels of AGR2 dimerization modulators are selectively deregulated, and this correlates with severity of disease.

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 proinflammatory responses.

EMBO Mol Med (2019) e10120

This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Marion Maurel, Joanna Obacz, Tony Avril, YongPing Ding, Olga Papadodima, Xavier Treton, Fanny Daniel, Eleftherios Pilalis, Johanna Hrberg, Wenyang Hou, MarieClaude Beauchamp, Julien TourneurMarsille, Dominique CazalsHatem, Lucia Sommerova, Afshin Samali, Jan Tavernier, Roman Hrstka, Aurlien Dupont, Delphine Fessart, Frdric Delom, Martin E FernandezZapico, Gregor Jansen, Leif A Eriksson, David Y Thomas, Loydie JeromeMajewska, Ted Hupp, Aristotelis Chatziioannou, Eric Chevet, Eric OgierDenis

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