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

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 TauntonNaoki Mochizuki, William Faubion, John P Cooke, Keigi Fujiwara, Scott E Evans, Nhat-Tu Le

Research output: Contribution to journalArticle

2 Citations (Scopus)

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.

Original languageEnglish (US)
JournalJCI Insight
Volume4
Issue number7
DOIs
StatePublished - Apr 4 2019
Externally publishedYes

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Endoplasmic Reticulum Stress
Atherosclerosis
Endothelial Cells
Activating Transcription Factor 6
90-kDa Ribosomal Protein S6 Kinases
Phosphorylation
SUMO-1 Protein
Guanylate Kinases
Apoptosis
Post Translational Protein Processing
Inflammatory Bowel Diseases
Aorta
Peptide Hydrolases
Chronic Disease
Epithelium
Macrophages
Inflammation
Pharmaceutical Preparations

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MAGI1 as a link between endothelial activation and ER stress drives atherosclerosis. / Abe, Jun-Ichi; Ko, Kyung Ae; Kotla, Sivareddy; Wang, Yin; Paez-Mayorga, Jesus; Shin, Ik Jae; Imanishi, Masaki; Vu, Hang Thi; Tao, Yunting; Leiva-Juarez, Miguel M; Thomas, Tamlyn N; Medina, Jan L; Won, Jong Hak; Fujii, Yuka; Giancursio, Carolyn J; McBeath, Elena; Shin, Ji-Hyun; Guzman, Liliana; Abe, Rei J; Taunton, Jack; Mochizuki, Naoki; Faubion, William; Cooke, John P; Fujiwara, Keigi; Evans, Scott E; Le, Nhat-Tu.

In: JCI Insight, Vol. 4, No. 7, 04.04.2019.

Research output: Contribution to journalArticle

Abe, J-I, Ko, KA, Kotla, S, Wang, Y, Paez-Mayorga, J, Shin, IJ, Imanishi, M, Vu, HT, Tao, Y, Leiva-Juarez, MM, Thomas, TN, Medina, JL, Won, JH, Fujii, Y, Giancursio, CJ, McBeath, E, Shin, J-H, Guzman, L, Abe, RJ, Taunton, J, Mochizuki, N, Faubion, W, Cooke, JP, Fujiwara, K, Evans, SE & Le, N-T 2019, 'MAGI1 as a link between endothelial activation and ER stress drives atherosclerosis', JCI Insight, vol. 4, no. 7. https://doi.org/10.1172/jci.insight.125570
Abe, Jun-Ichi ; Ko, Kyung Ae ; Kotla, Sivareddy ; Wang, Yin ; Paez-Mayorga, Jesus ; Shin, Ik Jae ; Imanishi, Masaki ; Vu, Hang Thi ; Tao, Yunting ; Leiva-Juarez, Miguel M ; Thomas, Tamlyn N ; Medina, Jan L ; Won, Jong Hak ; Fujii, Yuka ; Giancursio, Carolyn J ; McBeath, Elena ; Shin, Ji-Hyun ; Guzman, Liliana ; Abe, Rei J ; Taunton, Jack ; Mochizuki, Naoki ; Faubion, William ; Cooke, John P ; Fujiwara, Keigi ; Evans, Scott E ; Le, Nhat-Tu. / MAGI1 as a link between endothelial activation and ER stress drives atherosclerosis. In: JCI Insight. 2019 ; Vol. 4, No. 7.
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title = "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.",
author = "Jun-Ichi Abe and Ko, {Kyung Ae} and Sivareddy Kotla and Yin Wang and Jesus Paez-Mayorga and Shin, {Ik Jae} and Masaki Imanishi and Vu, {Hang Thi} and Yunting Tao and Leiva-Juarez, {Miguel M} and Thomas, {Tamlyn N} and Medina, {Jan L} and Won, {Jong Hak} and Yuka Fujii and Giancursio, {Carolyn J} and Elena McBeath and Ji-Hyun Shin and Liliana Guzman and Abe, {Rei J} and Jack Taunton and Naoki Mochizuki and William Faubion and Cooke, {John P} and Keigi Fujiwara and Evans, {Scott E} and Nhat-Tu Le",
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T1 - MAGI1 as a link between endothelial activation and ER stress drives atherosclerosis

AU - Abe, Jun-Ichi

AU - Ko, Kyung Ae

AU - Kotla, Sivareddy

AU - Wang, Yin

AU - Paez-Mayorga, Jesus

AU - Shin, Ik Jae

AU - Imanishi, Masaki

AU - Vu, Hang Thi

AU - Tao, Yunting

AU - Leiva-Juarez, Miguel M

AU - Thomas, Tamlyn N

AU - Medina, Jan L

AU - Won, Jong Hak

AU - Fujii, Yuka

AU - Giancursio, Carolyn J

AU - McBeath, Elena

AU - Shin, Ji-Hyun

AU - Guzman, Liliana

AU - Abe, Rei J

AU - Taunton, Jack

AU - Mochizuki, Naoki

AU - Faubion, William

AU - Cooke, John P

AU - Fujiwara, Keigi

AU - Evans, Scott E

AU - Le, Nhat-Tu

PY - 2019/4/4

Y1 - 2019/4/4

N2 - 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.

AB - 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.

U2 - 10.1172/jci.insight.125570

DO - 10.1172/jci.insight.125570

M3 - Article

C2 - 30944250

VL - 4

JO - JCI insight

JF - JCI insight

SN - 2379-3708

IS - 7

ER -