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Control of anterior GRadient 2 (AGR2) dimerization links endoplasmic reticulum proteostasis to inflammation

Journal article
Authors M. Maurel
J. Obacz
T. Avril
Y. P. Ding
O. Papadodima
X. Treton
F. Daniel
E. Pilalis
Johanna Hörberg
W. Y. Hou
M. C. Beauchamp
J. Tourneur-Marsille
D. Cazals-Hatem
L. Sommerova
A. Samali
J. Tavernier
R. Hrstka
A. Dupont
D. Fessart
F. Delom
M. E. Fernandez-Zapico
G. Jansen
Leif A Eriksson
D. Y. Thomas
L. Jerome-Majewska
T. Hupp
A. Chatziioannou
E. Chevet
E. Ogier-Denis
Published in EMBO Molecular Medicine
Volume 11
Issue 6
ISSN 1757-4676
Publication year 2019
Published at Department of Chemistry and Molecular Biology
Language en
Links dx.doi.org/10.15252/emmm.201810120
Keywords AGR2, endoplasmic reticulum, inflammation, proteostasis, TMED2, fast interaction refinement, unfolded protein response, particle mesh, ewald, dynamics, visualization, efficient, firedock, docking, family, Research & Experimental Medicine
Subject categories Biochemistry and Molecular Biology

Abstract

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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Utskriftsdatum: 2019-12-11