TY - JOUR
T1 - Control of anterior GRadient 2 (AGR2) dimerization links endoplasmic reticulum proteostasis to inflammation
AU - Maurel, Marion
AU - Obacz, Joanna
AU - Avril, Tony
AU - Ding, Yong Ping
AU - Papadodima, Olga
AU - Treton, Xavier
AU - Daniel, Fanny
AU - Pilalis, Eleftherios
AU - Hörberg, Johanna
AU - Hou, Wenyang
AU - Beauchamp, Marie Claude
AU - Tourneur-Marsille, Julien
AU - Cazals-Hatem, Dominique
AU - Sommerova, Lucia
AU - Samali, Afshin
AU - Tavernier, Jan
AU - Hrstka, Roman
AU - Dupont, Aurélien
AU - Fessart, Delphine
AU - Delom, Frédéric
AU - Fernandez-Zapico, Martin E.
AU - Jansen, Gregor
AU - Eriksson, Leif A.
AU - Thomas, David Y.
AU - Jerome-Majewska, Loydie
AU - Hupp, Ted
AU - Chatziioannou, Aristotelis
AU - Chevet, Eric
AU - Ogier-Denis, Eric
N1 - Publisher Copyright:
© 2019 The Authors. Published under the terms of the CC BY 4.0 license
PY - 2019/6
Y1 - 2019/6
N2 - 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.
AB - 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.
KW - AGR2
KW - TMED2
KW - endoplasmic reticulum
KW - inflammation
KW - proteostasis
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UR - http://www.scopus.com/inward/citedby.url?scp=85065188436&partnerID=8YFLogxK
U2 - 10.15252/emmm.201810120
DO - 10.15252/emmm.201810120
M3 - Article
C2 - 31040128
AN - SCOPUS:85065188436
SN - 1757-4676
VL - 11
JO - EMBO Molecular Medicine
JF - EMBO Molecular Medicine
IS - 6
M1 - e10120
ER -