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

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 9

MAGI1 regulates nuclear ATF6 translocation induced by treatment with Thb.

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MAGI1 regulates nuclear ATF6 translocation induced by treatment with Thb...
(A and B) HUVECs treated with siRNA were stimulated with Thb (1 h). Thb induced nuclear ATF6 localization, as indicated by immunostaining of cells with anti-ATF6. ATF6 nuclear translocation was inhibited by treatment with MAGI1 siRNA (siMAGI1). Scale bars: 20 μm. (B) Quantification of the percentage of cells with nuclear ATF6 localization. Data represent mean ± SEM. **P < 0.01. siCont, control siRNA. (C and D) HUVECs were treated with ATF6 or control siRNA for 48 hours and transduced with an adenovirus containing WT p90RSK (Ad-WT-p90RSK), MAGI1-WT (Ad-WT-MAGI1), the MAGI1-K931R mutant (Ad-MAGI1-K931R), or LacZ as a control. p90RSK, MAGI1, and ATF6 expression were detected using Western blotting, as indicated in C. Sixteen hours later, EC apoptosis was evaluated according to annexin V expression, as described in Methods. Data represent mean ± SEM (n = 6) **P < 0.01. (E) Schematic of the role of MAGI1 PTMs in regulation of EC activation. Proatherogenic stimuli activate p90RSK, independently increasing MAGI1-S741 phosphorylation and MAGI1-K931 deSUMOylation. MAGI1-S741 phosphorylation increases Rap1 activation in the cytosol, whereas MAGI1-K931 deSUMOylation induces nuclear cotranslocation of the p90RSK- or ATF6-MAGI1 complex and instigates nuclear events such as increased binding of nuclear p90RSK to ERK5, which inhibits the atheroprotective function of ERK5, and XBP-1 expression induced by nuclear ATF6 translocation. These events lead to EC activation and apoptosis and subsequent atherosclerotic plaque formation. X, disruption of MAGI1 SUMOylation. Statistical differences were assessed using 1-way ANOVA followed by Bonferroni’s post hoc testing for multiple groups.