Journal
EMBO MOLECULAR MEDICINE
Volume 11, Issue 6, Pages -Publisher
WILEY
DOI: 10.15252/emmm.201810120
Keywords
AGR2; endoplasmic reticulum; inflammation; proteostasis; TMED2
Categories
Funding
- INSERM, Institut National du Cancer [PLBIO INCa_5869]
- Rennes Metropole
- Canceropole Grand Sud-Ouest
- EU H2020 [MSCA ITN-675448, MSCA RISE-734749]
- Swedish Research Council [2014-3914]
- Association Francois Aupetit (AFA)
- Universite Diderot Paris 7
- Investissements d'Avenir programme, Sorbonne Paris Cite, Laboratoire d'excellence INFLAMEX [ANR-11-IDEX-0005-02]
- GACR [19-02014S]
- PROMISE [12CHN 204]
- Chinese Ministry of Research and Technology - Program Competitiveness and Entrepreneurship, Priority Health of the Peripheral Entrepreneurial Program of Attiki
- FWO
- INCa
- Region Bretagne
- Canadian Institutes of Health Research
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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.
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