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

M Maurel ,Delphine Fessart,Frédéric Delom,Tony Avril,Fanny Daniel,Olga Papadodima,Wenyang Hou,Aurélien Dupont,Johanna Hörberg,Gregor Jansen,Joanna Obacz,Afshin Samali,Aristotelis Chatziioannou,Jan Tavernier,Roman Hrstka,Eleftherios Pilalis,Lucia Sommerová ,Ted R Hupp ,Marie‐Eve Beauchamp ,Dominique Cazals–Hatem ,Julien Tourneur‐Marsille ,Éric Chevet ,Leif A Eriksson ,Loydie A Jerome-Majewska ,Yingtao Ding ,David Y Thomas ,Xavier Tréton ,Martín E Fernández-Zapico ,Éric Ogier–Denis

doi:10.15252/emmm.201810120

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.

Highlights

The regulation of protein homeostasis in the endoplasmic reticulum (ER) has recently emerged as an important pathophysiological mechanism involved in the development of different diseases (Hetz et al, 2015)
Since Anterior gradient 2 (AGR2) is involved in protein quality control in the ER (Higa et al, 2011), we evaluated the impact of ER homeostasis disruption on AGR2 dimerization
Among the positive regulators of AGR2 dimerization found in the screen (Fig 2), we identified TMED2, a p24 family member previously shown to function as a cargo receptor (Barlowe, 1998)

Summary

Introduction

The regulation of protein homeostasis (proteostasis) in the endoplasmic reticulum (ER) has recently emerged as an important pathophysiological mechanism involved in the development of different diseases (Hetz et al, 2015). Anterior gradient 2 (AGR2), a folding catalyst, binds to nascent protein chains, and it is required for the maintenance of ER homeostasis (Persson et al, 2005; Higa et al, 2011; Chevet et al, 2013). Anterior gradient proteins, including AGR2, were identified more than a decade ago, their precise biological functions remain ill-defined. Biochemical approaches have shown that AGR2 forms dimers (Ryu et al, 2012; Patel et al, 2013). As such, this justifies an in-depth study to characterize the protein– protein interaction-dependent regulatory mechanisms controlling AGR2 dimerization and functions

Methods

Results

Conclusion