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

Marion Maurel, Joanna Obacz, Tony Avril, Yong Ping Ding, Olga Papadodima, Xavier Treton, Fanny Daniel, Eleftherios Pilalis, Johanna Hörberg, Wenyang Hou, Marie Claude Beauchamp, Julien Tourneur-Marsille, Dominique Cazals-Hatem, Lucia Sommerova, Afshin Samali, Jan Tavernier, Roman Hrstka, Aurélien Dupont, Delphine Fessart, Frédéric DelomMartin E Fernandez-Zapico, Gregor Jansen, Leif A. Eriksson, David Y. Thomas, Loydie Jerome-Majewska, Ted Hupp, Aristotelis Chatziioannou, Eric Chevet, Eric Ogier-Denis

Research output: Contribution to journalArticle

4 Citations (Scopus)

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.

Original languageEnglish (US)
Article numbere10120
JournalEMBO Molecular Medicine
Volume11
Issue number6
DOIs
StatePublished - Jun 1 2019

Fingerprint

Dimerization
Endoplasmic Reticulum
Inflammation
Inflammatory Bowel Diseases
Protein Disulfide-Isomerases
Endoplasmic Reticulum Stress
Secretory Pathway
Autophagy
Crohn Disease
Quality Control
Homeostasis
Phenotype
Proteins

Keywords

  • AGR2
  • endoplasmic reticulum
  • inflammation
  • proteostasis
  • TMED2

ASJC Scopus subject areas

  • Molecular Medicine

Cite this

Maurel, M., Obacz, J., Avril, T., Ding, Y. P., Papadodima, O., Treton, X., ... Ogier-Denis, E. (2019). Control of anterior GRadient 2 (AGR2) dimerization links endoplasmic reticulum proteostasis to inflammation. EMBO Molecular Medicine, 11(6), [e10120]. https://doi.org/10.15252/emmm.201810120

Control of anterior GRadient 2 (AGR2) dimerization links endoplasmic reticulum proteostasis to inflammation. / Maurel, Marion; Obacz, Joanna; Avril, Tony; Ding, Yong Ping; Papadodima, Olga; Treton, Xavier; Daniel, Fanny; Pilalis, Eleftherios; Hörberg, Johanna; Hou, Wenyang; Beauchamp, Marie Claude; Tourneur-Marsille, Julien; Cazals-Hatem, Dominique; Sommerova, Lucia; Samali, Afshin; Tavernier, Jan; Hrstka, Roman; Dupont, Aurélien; Fessart, Delphine; Delom, Frédéric; Fernandez-Zapico, Martin E; Jansen, Gregor; Eriksson, Leif A.; Thomas, David Y.; Jerome-Majewska, Loydie; Hupp, Ted; Chatziioannou, Aristotelis; Chevet, Eric; Ogier-Denis, Eric.

In: EMBO Molecular Medicine, Vol. 11, No. 6, e10120, 01.06.2019.

Research output: Contribution to journalArticle

Maurel, M, Obacz, J, Avril, T, Ding, YP, Papadodima, O, Treton, X, Daniel, F, Pilalis, E, Hörberg, J, Hou, W, Beauchamp, MC, 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 2019, 'Control of anterior GRadient 2 (AGR2) dimerization links endoplasmic reticulum proteostasis to inflammation', EMBO Molecular Medicine, vol. 11, no. 6, e10120. https://doi.org/10.15252/emmm.201810120
Maurel, Marion ; Obacz, Joanna ; Avril, Tony ; Ding, Yong Ping ; Papadodima, Olga ; Treton, Xavier ; Daniel, Fanny ; Pilalis, Eleftherios ; Hörberg, Johanna ; Hou, Wenyang ; Beauchamp, Marie Claude ; Tourneur-Marsille, Julien ; Cazals-Hatem, Dominique ; Sommerova, Lucia ; Samali, Afshin ; Tavernier, Jan ; Hrstka, Roman ; Dupont, Aurélien ; Fessart, Delphine ; Delom, Frédéric ; Fernandez-Zapico, Martin E ; Jansen, Gregor ; Eriksson, Leif A. ; Thomas, David Y. ; Jerome-Majewska, Loydie ; Hupp, Ted ; Chatziioannou, Aristotelis ; Chevet, Eric ; Ogier-Denis, Eric. / Control of anterior GRadient 2 (AGR2) dimerization links endoplasmic reticulum proteostasis to inflammation. In: EMBO Molecular Medicine. 2019 ; Vol. 11, No. 6.
@article{c02adf23edce4d6db3778e3de905061b,
title = "Control of anterior GRadient 2 (AGR2) dimerization links endoplasmic reticulum proteostasis to inflammation",
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.",
keywords = "AGR2, endoplasmic reticulum, inflammation, proteostasis, TMED2",
author = "Marion Maurel and Joanna Obacz and Tony Avril and Ding, {Yong Ping} and Olga Papadodima and Xavier Treton and Fanny Daniel and Eleftherios Pilalis and Johanna H{\"o}rberg and Wenyang Hou and Beauchamp, {Marie Claude} and Julien Tourneur-Marsille and Dominique Cazals-Hatem and Lucia Sommerova and Afshin Samali and Jan Tavernier and Roman Hrstka and Aur{\'e}lien Dupont and Delphine Fessart and Fr{\'e}d{\'e}ric Delom and Fernandez-Zapico, {Martin E} and Gregor Jansen and Eriksson, {Leif A.} and Thomas, {David Y.} and Loydie Jerome-Majewska and Ted Hupp and Aristotelis Chatziioannou and Eric Chevet and Eric Ogier-Denis",
year = "2019",
month = "6",
day = "1",
doi = "10.15252/emmm.201810120",
language = "English (US)",
volume = "11",
journal = "EMBO Molecular Medicine",
issn = "1757-4676",
publisher = "Wiley-Blackwell",
number = "6",

}

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

PY - 2019/6/1

Y1 - 2019/6/1

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 - endoplasmic reticulum

KW - inflammation

KW - proteostasis

KW - TMED2

UR - http://www.scopus.com/inward/record.url?scp=85065188436&partnerID=8YFLogxK

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

VL - 11

JO - EMBO Molecular Medicine

JF - EMBO Molecular Medicine

SN - 1757-4676

IS - 6

M1 - e10120

ER -