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

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

doi:10.1172/jci.insight.125570

Cited by 44 publications

(61 citation statements)

References 47 publications

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“…The p90 ribosomal S6 kinase (p90RSK) signaling cascade has been demonstrated to play an essential role in multiple cellular functions with the ability to phosphorylate and regulate the activity of many transcriptional factors and kinases. In a previous study, we found that p90RSK directly phosphorylates MAGI1 S741 and causes MAGI1 de-SUMOylation at K931, leading to EC activation (29). In this study, we will examine whether these p90RSK-dependent MAGI1 post-translational modifications (PTMs) impact EC barrier functions.…”

Section: Introductionmentioning

confidence: 98%

p90RSK-MAGI1 Module Controls Endothelial Permeability by Post-translational Modifications of MAGI1 and Hippo Pathway

Abe

Savage

Imanishi

et al. 2020

Front. Cardiovasc. Med.

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Previously, we reported that post-translational modifications (PTMs) of MAGI1, including S741 phosphorylation and K931 de-SUMOylation, both of which are regulated by p90RSK activation, lead to endothelial cell (EC) activation. However, roles for p90RSK and MAGI1-PTMs in regulating EC permeability remain unclear despite MAGI1 being a junctional molecule. Here, we show that thrombin (Thb)-induced EC permeability, detected by the electric cell-substrate impedance sensing (ECIS) based system, was decreased by overexpression of dominant negative p90RSK or a MAGI1-S741A phosphorylation mutant, but was accelerated by overexpression of p90RSK, siRNA-mediated knockdown of magi1, or the MAGI1-K931R SUMOylation mutant. MAGI1 depletion also increased the mRNA and protein expression of the large tumor suppressor kinases 1 and 2 (LATS1/2), which inhibited YAP/TAZ activity and increased EC permeability. Because the endothelial barrier is a critical mediator of tumor hypoxia, we also evaluated the role of p90RSK activation in tumor vessel leakiness by using a relatively low dose of the p90RSK specific inhibitor, FMK-MEA. FMK-MEA significantly inhibited tumor vessel leakiness at a dose that does not affect morphology and growth of tumor vessels in vivo. These results provide novel insights into crucial roles for p90RSK-mediated MAGI1 PTMs and the Hippo pathway in EC permeability, as well as p90RSK activation in tumor vessel leakiness.

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Section: Introductionmentioning

confidence: 98%

p90RSK-MAGI1 Module Controls Endothelial Permeability by Post-translational Modifications of MAGI1 and Hippo Pathway

Abe

Savage

Imanishi

et al. 2020

Front. Cardiovasc. Med.

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“…ER stress was chosen because ubiquitin D, encoded by UBD, is involved in the ER stress response, and risk-variant APOL1 appears to localize to the ER membrane 30 . Furthermore, ER stress is becoming an increasingly recognized driver of complex diseases, including CKD [31][32][33][34] . To induce ER stress, we treated organoids with 5 µM tunicamycin for 24 hours and observed increased expression of unfolded protein response genes EDEM1 and HSPA5 by RT-qPCR ( Figure 4A).…”

Section: Resultsmentioning

confidence: 99%

ProfilingAPOL1Nephropathy Risk Variants in Genome-Edited Kidney Organoids with Single-Cell Transcriptomics

Liu

Radmanesh

Chung

et al. 2019

Preprint

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Running Title: APOL1 Variant Organoid scRNA-seq Word Count: 205 (Abstract), 1736 (Main Text, excluding Methods)ABSTRACT Background DNA variants in APOL1 associate with kidney disease, but the pathophysiological mechanisms remain incompletely understood. Model organisms lack the APOL1 gene, limiting the degree to which disease states can be recapitulated. Here we present single-cell RNA sequencing (scRNAseq) of genome-edited human kidney organoids as a platform for profiling effects of APOL1 risk variants in diverse nephron cell types. MethodsWe performed footprint-free CRISPR-Cas9 genome editing of human induced pluripotent stem cells (iPSCs) to knock in APOL1 high-risk G1 variants at the native genomic locus. iPSCs were differentiated into kidney organoids, treated with vehicle, IFN-g, or the combination of IFN-g and tunicamycin, and analyzed with scRNA-seq to profile cell-specific changes in differential gene expression patterns, compared to isogenic G0 controls. ResultsBoth G0 and G1 iPSCs differentiated into kidney organoids containing nephron-like structures with glomerular epithelial cells, proximal tubules, distal tubules, and endothelial cells.Organoids expressed detectable APOL1 only after exposure to IFN-g. scRNA-seq revealed cell type-specific differences in G1 organoid response to APOL1 induction. Additional stress of tunicamycin exposure led to increased glomerular epithelial cell dedifferentiation in G1 organoids. ConclusionsSingle-cell transcriptomic profiling of human genome-edited kidney organoids expressing APOL1 risk variants provides a novel platform for studying the pathophysiology of APOL1mediated kidney disease.

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“…Ocular involvement in sarcoidosis has been highlighted recently in a large GWAS screening identifying seven variants in the MAGI1 (membrane associated guanylate kinase with inverted structure 1) gene, encoding an adaptor protein that stabilizes epithelial and endothelial cell-cell contacts mainly through the PTEN/phosphatidylinositol-3 kinase/Akt and β-catenin pathways [34]. MAGI1 has been related to tumor progression in various cancers and to autoimmune diseases in rat models and in human psoriatic arthritis [80].…”

Section: Other Pathways Identified By Gwas In Sarcoidosis Etiologymentioning

confidence: 99%

Current Insights in Genetics of Sarcoidosis: Functional and Clinical Impacts

Calender

Weichhart

Valeyre

et al. 2020

JCM

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Sarcoidosis is a complex disease that belongs to the vast group of autoinflammatory disorders, but the etiological mechanisms of which are not known. At the crosstalk of environmental, infectious, and genetic factors, sarcoidosis is a multifactorial disease that requires a multidisciplinary approach for which genetic research, in particular, next generation sequencing (NGS) tools, has made it possible to identify new pathways and propose mechanistic hypotheses. Codified treatments for the disease cannot always respond to the most progressive forms and the identification of new genetic and metabolic tracks is a challenge for the future management of the most severe patients. Here, we review the current knowledge regarding the genes identified by both genome wide association studies (GWAS) and whole exome sequencing (WES), as well the connection of these pathways with the current research on sarcoidosis immune-related disorders.

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

Abstract: Conflict of interest: JT is a cofounder of Principia Biopharma, which has licensed the p90RSK inhibitor FMK-MEA.

Cited by 44 publications

References 47 publications

p90RSK-MAGI1 Module Controls Endothelial Permeability by Post-translational Modifications of MAGI1 and Hippo Pathway

p90RSK-MAGI1 Module Controls Endothelial Permeability by Post-translational Modifications of MAGI1 and Hippo Pathway

ProfilingAPOL1Nephropathy Risk Variants in Genome-Edited Kidney Organoids with Single-Cell Transcriptomics

Current Insights in Genetics of Sarcoidosis: Functional and Clinical Impacts

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