1. Control of anterior GRadient 2 (AGR2) dimerization links endoplasmic reticulum proteostasis to inflammation
- Author
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Maurel, M, Obacz, J, Avril, T, Ding, Y-P, Papadodima, O, Treton, X, Daniel, F, Pilalis, E, Hörberg, J, Hou, W, Beauchamp, M-C, Tourneur-Marsille, J, Cazals-Hatem, D, Sommerova, L, Samali, A, Tavernier, J, Hrstka, R, Dupont, A, Fessart, D, Delom, F, Fernandez-Zapico, ME, Jansen, G, Eriksson, LA, Thomas, DY, Jerome-Majewska, L, Hupp, T, Chatziioannou, A, Chevet, E, Ogier-Denis, E, Chemistry, Oncogenesis, Stress and Signaling (COSS), Institut National de la Santé et de la Recherche Médicale (INSERM)-CRLCC Eugène Marquis (CRLCC)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Universiteit Gent = Ghent University [Belgium] (UGENT), Centre Eugène Marquis (CRLCC), Centre de recherche sur l'Inflammation (CRI (UMR_S_1149 / ERL_8252 / U1149)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Hôpital Raymond Poincaré [AP-HP], University of Gothenburg (GU), McGill University = Université McGill [Montréal, Canada], Biosit : biologie, santé, innovation technologique (SFR UMS CNRS 3480 - INSERM 018), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Centre de Microscopie de Rennes (MRic), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Schulze Center for Novel Therapeutics, Division of Oncology Research [Rochester], Mayo Clinic [Rochester], CRLCC Eugène Marquis (CRLCC), RISE‐734749, H2020 Marie Skłodowska-Curie Actions, Canadian Institutes of Health Research, Fonds Wetenschappelijk Onderzoek, ANR‐11‐IDEX‐0005‐02, Agence Nationale de la Recherche, 2014‐3914, Svenska Forskningsrådet Formas, Institut National de la Santé et de la Recherche Médicale, 2014‐3914, Vetenskapsrådet, PLBIO INCa_5869, Institut National Du Cancer, 19‐02014S, Grantová Agentura České Republiky, Région Bretagne, Jonchère, Laurent, Université de Rennes (UR)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Universiteit Gent = Ghent University (UGENT), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de Rennes (UR)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), and ANR-11-IDEX-0005,USPC,Université Sorbonne Paris Cité(2011)
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Male ,TMED2 ,Medicine (General) ,Immunology ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,QH426-470 ,Endoplasmic Reticulum ,Mice ,R5-920 ,Mucoproteins ,[SDV.CAN] Life Sciences [q-bio]/Cancer ,Genetics ,Animals ,Humans ,Research Articles ,Oncogene Proteins ,proteostasis ,Endoplasmic Reticulum Stress ,proteostatis ,endoplasmic reticulum ,HEK293 Cells ,Metabolism ,inflammation ,Protein Multimerization ,Digestive System ,Research Article ,AGR2 - Abstract
International audience; 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.
- Published
- 2019
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