MAGI1 as a link between endothelial activation and ER stress drives atherosclerosis
Jun-ichi Abe, … , Scott E. Evans, Nhat-Tu Le
Jun-ichi Abe, … , Scott E. Evans, Nhat-Tu Le
Published April 4, 2019
Citation Information: JCI Insight. 2019;4(7):e125570. https://doi.org/10.1172/jci.insight.125570.
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Research Article Cardiology Cell biology Article has an altmetric score of 2

MAGI1 as a link between endothelial activation and ER stress drives atherosclerosis

Abstract

The possible association between the membrane-associated guanylate kinase with inverted domain structure-1 (MAGI1) and inflammation has been suggested, but the molecular mechanisms underlying this link, especially during atherogenesis, remain unclear. In endothelial cells (ECs) exposed to disturbed flow (d-flow), p90 ribosomal S6 kinase (p90RSK) bound to MAGI1, causing MAGI1-S741 phosphorylation and sentrin/SUMO-specific protease 2 T368 phosphorylation-mediated MAGI1-K931 deSUMOylation. MAGI1-S741 phosphorylation upregulated EC activation via activating Rap1. MAGI1-K931 deSUMOylation induced both nuclear translocation of p90RSK-MAGI1 and ATF-6-MAGI1 complexes, which accelerated EC activation and apoptosis, respectively. Microarray screening revealed key roles for MAGI1 in the endoplasmic reticulum (ER) stress response. In this context, MAGI1 associated with activating transcription factor 6 (ATF-6). MAGI1 expression was upregulated in ECs and macrophages found in atherosclerotic-prone regions of mouse aortas as well as in the colonic epithelia and ECs of patients with inflammatory bowel disease. Further, reduced MAGI1 expression in Magi1–/+ mice inhibited d-flow–induced atherogenesis. In sum, EC activation and ER stress–mediated apoptosis are regulated in concert by two different types of MAGI1 posttranslational modifications, elucidating attractive drug targets for chronic inflammatory disease, particularly atherosclerosis.

Authors

Jun-ichi Abe, Kyung Ae Ko, Sivareddy Kotla, Yin Wang, Jesus Paez-Mayorga, Ik Jae Shin, Masaki Imanishi, Hang Thi Vu, Yunting Tao, Miguel M. Leiva-Juarez, Tamlyn N. Thomas, Jan L. Medina, Jong Hak Won, Yuka Fujii, Carolyn J. Giancursio, Elena McBeath, Ji-Hyun Shin, Liliana Guzman, Rei J. Abe, Jack Taunton, Naoki Mochizuki, William Faubion, John P. Cooke, Keigi Fujiwara, Scott E. Evans, Nhat-Tu Le

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Figure 4

The role of p90RSK-mediated MAGI1-S741 phosphorylation in regulating Rap1 activation.

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The role of p90RSK-mediated MAGI1-S741 phosphorylation in regulating Rap...
(A) Activation of the small GTPase Rap1 in d-flow–induced NF-κB activation. HUVECs expressing a DN form of Rap1 (Rap-N17) were subjected to an NF-κB activity assay with d-flow stimulation (24 h), and the relative NF-κB luciferase activity in the cells was measured. Data represent mean ± SEM (n = 6). **P < 0.01. (B–D) p90RSK activation and MAGI1-S741 phosphorylation in ECs with d-flow–induced Rap1 activation. ECs transduced with Ad-LacZ or Ad-Flag-DN-p90RSK (B) or Ad-Flag-MAGI1-WT or Ad-Flag– MAGI1-S741A (C) (MOI, 20) were exposed to d-flow for the indicated times (B) or 20 minutes (C). The level of Rap1-GTP expression in ECs was measured using Rap1 pull-down assays (above the dotted line). The levels of total Rap1, DN-p90RSK, MAGI1, and tubulin expression were determined using IB (B, below the dotted line). Shown are representative blots from 3 independent experiments. (D) The Rap1-GTP expression level in C was quantified (n = 3). Data represent mean ± SEM. *P < 0.01. Statistical differences were assessed using 1-way ANOVA followed by Bonferroni’s post hoc testing for multiple groups.