Control of anterior GRadient 2 (AGR2) dimerization links endoplasmic reticulum proteostasis to inflammation - Université de Rennes Access content directly
Journal Articles EMBO Molecular Medicine Year : 2019

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

Olga Papadodima
  • Function : Author
Eleftherios Pilalis
  • Function : Author
Lucia Sommerova
  • Function : Author
Afshin Samali
  • Function : Author
Jan Tavernier
Roman Hrstka
  • Function : Author
Delphine Fessart
  • Function : Author
Frédéric Delom
  • Function : Author
Ted Hupp
  • Function : Author
Aristotelis Chatziioannou
  • Function : Correspondent author
Eric Chevet

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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hal-02160377 , version 1 (10-07-2020)

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Marion Maurel, Joanna Obacz, Tony Avril, Yong-Ping Ding, Olga Papadodima, et al.. Control of anterior GRadient 2 (AGR2) dimerization links endoplasmic reticulum proteostasis to inflammation. EMBO Molecular Medicine, 2019, 11 (6), pp.e10120. ⟨10.15252/emmm.201810120⟩. ⟨hal-02160377⟩
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