前GRadient 2（AGR2）二聚化的控制将内质网蛋白稳态与炎症联系起来。,EMBO Molecular Medicine

当前位置： X-MOL 学术 › EMBO Mol. Med. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

前GRadient 2（AGR2）二聚化的控制将内质网蛋白稳态与炎症联系起来。
EMBO Molecular Medicine ( IF 9.0 ) Pub Date : 2019-06-01 , DOI: 10.15252/emmm.201810120
Marion Maurel _{1,

2,

3,

4} , Joanna Obacz _{1,

2} , Tony Avril _{1,

2} , Yong-Ping Ding _{5,

6,

7} , Olga Papadodima ₈ , Xavier Treton _{5,

6,

7} , Fanny Daniel _{5,

6,

7} , Eleftherios Pilalis _{8,

9} , Johanna Hörberg ₁₀ , Wenyang Hou ₁₁ , Marie-Claude Beauchamp ₁₁ , Julien Tourneur-Marsille _{5,

6,

7} , Dominique Cazals-Hatem _{5,

6,

7} , Lucia Sommerova ₁₂ , Afshin Samali ₄ , Jan Tavernier ₃ , Roman Hrstka ₁₂ , Aurélien Dupont ₁₃ , Delphine Fessart ₁₄ , Frédéric Delom ₁₄ , Martin E Fernandez-Zapico ₁₅ , Gregor Jansen ₁₆ , Leif A Eriksson ₁₀ , David Y Thomas ₁₆ , Loydie Jerome-Majewska ₁₁ , Ted Hupp _{9,

12,

17} , Aristotelis Chatziioannou _{18,

19} , Eric Chevet _{2,

20} , Eric Ogier-Denis _{6,

7,

21}

Affiliation

INSERM U1242, "Chemistry, Oncogenesis Stress Signaling", University of Rennes, Rennes, France.
Centre de Lutte Contre le Cancer Eugène Marquis, Rennes, France.
VIB Department of Medical Protein Research, UGent, Gent, Belgium.
Apoptosis Research Centre, School of Natural Sciences, NUI Galway, Galway, Ireland.
INSERM, UMR1149, Team «Gut Inflammation», Research Centre of Inflammation, Paris, France.
Université Paris-Diderot Sorbonne Paris-Cité, Paris, France.
APHP Beaujon Hospital Clichy la Garenne, Paris, France.
Institute of Biology, Medicinal Chemistry & Biotechnology, NHRF, Athens, Greece.
International Centre for Cancer Vaccine Science, Gdansk, Poland.
Department of Chemistry and Molecular Biology, University of Gothenburg, Göteborg, Sweden.
Departments of Anatomy and Cell Biology, Human Genetics, and Pediatrics, McGill University, Montreal, QC, Canada.
Regional Centre for Applied Molecular Oncology (RECAMO), Brno, Czech Republic.
Microscopy Rennes Imaging Centre, and Biosit, UMS3480 CNRS, University of Rennes 1, Rennes Cédex, France.
University of Bordeaux, Bordeaux, France.
Division of Oncology Research, Department of Oncology, Schulze Center for Novel Therapeutics, Mayo Clinic, Rochester, MN, USA.
Biochemistry Department, McGill University Life Sciences Complex, Montréal, QC, Canada.
Edinburgh Cancer Research Centre at the Institute of Genetics and Molecular Medicine, Edinburgh University, Edimburgh, UK.
Institute of Biology, Medicinal Chemistry & Biotechnology, NHRF, Athens, Greece
e-NIOS PC, Kallithea-Athens, Greece.
INSERM U1242, "Chemistry, Oncogenesis Stress Signaling", University of Rennes, Rennes, France
INSERM, UMR1149, Team «Gut Inflammation», Research Centre of Inflammation, Paris, France

前梯度2（AGR2）是二聚体蛋白质二硫键异构酶家族成员，参与内质网（ER）蛋白质质量控制的调节。小鼠AGR2缺失会增加肠道炎症并促进炎症性肠病（IBD）的发展。尽管这些生物学作用已得到很好的确立，但AGR2对炎症的潜在分子机制仍不清楚。在这里，我们使用蛋白质-蛋白质相互作用筛选来识别AGR2二聚化的细胞调节剂，我们揭示了控制AGR2功能的特定增强子，包括TMED2和AGR2二聚化抑制剂。我们证明，无论是增强还是抑制该过程，AGR2二聚体形成的调节都会产生促炎表型，通过自噬依赖性过程或AGR2的分泌。我们还证明，在IBD中，特别是在克罗恩氏病中，AGR2二聚体调节剂的水平被选择性地解除调节，这与疾病的严重程度相关。我们的研究表明，AGR2二聚体可作为ER稳态的传感器，后者在ER应力作用下被破坏并促进AGR2单体的分泌。后者可能代表促炎反应的全身性警报信号。我们的研究表明，AGR2二聚体可作为ER稳态的传感器，后者在ER应力作用下被破坏并促进AGR2单体的分泌。后者可能代表促炎反应的全身性警报信号。我们的研究表明，AGR2二聚体可作为ER稳态的传感器，后者在ER应力作用下被破坏并促进AGR2单体的分泌。后者可能代表促炎反应的全身性警报信号。

"点击查看英文标题和摘要"

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

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.

更新日期：2019-06-21

点击分享查看原文

点击收藏

公开下载

阅读更多本刊新发论文本刊介绍/投稿指南