A Novel Role for MAGI1 in regulating non-canonical LATS signaling and atherosclerotic plaque formation

MAGI1 在调节非经典 LATS 信号传导和动脉粥样硬化斑块形成中的新作用

基本信息

批准号：
10112287
负责人：
Nhat-Tu Le
金额：
$ 38.06万
依托单位：
METHODIST HOSPITAL RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-01-01 至 2023-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10112287
关键词：
Adherens Junction Apoptosis Arterial Fatty Streak Atherosclerosis Attenuated BAIAP1 gene Binding Cardiovascular Diseases Carotid Arteries Cell Death Cell Nucleus Clinical Complex Cytosol DLG4 gene Data Endothelial Cells Endothelium Event Functional disorder Gene Expression Goals Growth Factor Guanylate kinase Human Inflammation Inflammatory Inflammatory Bowel Diseases Intestines Knock-in Knock-in Mouse Knock-out Knockout Mice Lead Ligation Link MAPK7 gene Mediating Modification Molecular Mus Mutation Nuclear Nuclear Accidents Nuclear Translocation Outcome Pathway interactions Phenotype Phosphorylation Phosphotransferases Play Post-Translational Protein Processing Prevention Proteins Psoriasis Psoriatic Arthritis Reactive Oxygen Species Reporting Role SUMO1 gene Scaffolding Protein Severity of illness Signal Pathway Signal Transduction Stimulus Sumoylation Pathway TNF gene Testing Thrombin Tight Junctions Transactivation Tumor Suppressor Proteins atherogenesis cardiovascular disorder risk cytokine genome wide association study genome-wide genomic locus guanylate kinase 1 membrane-associated guanylate kinase novel novel therapeutic intervention therapeutic target vascular inflammation

项目摘要

Project Summary Pro-atherogenic stimuli such as inflammatory cytokines and disturbed flow (d-flow) significantly contribute to endothelial cell (EC) inflammation, and subsequent atherosclerotic plaque formation. Membrane-associated guanylate kinase-1 (MAGI1) is a scaffold protein that contains six PSD95/DiscLarge/ZO-1 (PDZ) domains, a guanylate kinase domain, and two WW domains flanked by the first and second PDZ domains. MAGI1 associates with the tight and adherens junction, but its cytosolic and nuclear localization has also been reported. Recently, a genome-wide association study has revealed a strong association of mutations in Magi1 gene locus with inflammatory bowel disease and psoriatic arthritis. The significant contribution of EC inflammation in regulating the phenotype and severity of these diseases, which are also clinically associated with accelerated atherosclerosis (AS) and increased risk of cardiovascular diseases, has been well established. In the preliminary data, we have found the critical role of MAGI1 post-translational modifications (PTMs) in regulating EC inflammation and apoptosis. MAGI1 S741 phosphorylarion results in the activation of Rap1 and large tumor suppressor 1 (LATS1) (but not Yes-associated protein [YAP] phosphorylation, which is a canonical pathway regulated by LATS1). MAGI1 de-SUMOylation leads to the co-translocation of MAGI1 and p90RSK to the nucleus, where they up-regulate inflammatory gene expression. In the proposed study, we hypothesize that dynamic modulation of MAGI1 PTMs (phosphorylation and de-SUMOylation) leads to cytosolic Rap1 and non- canonical LATSs signaling activation, and p90RSK nuclear translocation. MAGI1 in both cytosolic and nuclear compartments plays critical roles in regulating EC inflammation and apoptosis and subsequent atherogenesis. Aim 1 will identify the mechanism by which MAGI1 S741 phosphorylation promotes EC inflammation and apoptosis. Aim 2 will determine the role of MAGI1 de-SUMOylation in nuclear translocation and promoting EC inflammation. In aim 3, we will determine the role of MAGI1 and LATS1/2 in accelerating AS. The concept of the MAGI1 PTMs including phosphorylation- and de-SUMOylation-induced EC inflammation is novel and highlights the importance of determining how this PDZ domain-containing molecule and p90RSK coordinately regulate EC inflammation and apoptosis. The long–term goals of this project are to identify the role of MAGI1 phosphorylation and (de)SUMOylation in regulating MAGI1 subcellular localization and MAGI1-dependent signaling and to elucidate the molecular mechanisms by which MAGI1 induces EC inflammation and apoptosis and promotes atherogenesis. This will provide deeper understanding of the basic signaling responsible for the poor outcome of AS-related cardiovascular diseases.

项目概要促动脉粥样硬化刺激，例如炎性细胞因子和血流紊乱（d-flow）显着促进内皮细胞（EC）炎症，以及随后的动脉粥样硬化斑块形成。鸟苷酸激酶-1 (MAGI1) 是一种支架蛋白，包含六个 PSD95/DiscLarge/ZO-1 (PDZ) 结构域，鸟苷酸激酶结构域和两个 WW 结构域，两侧分别是第一个和第二个 MAGI1 结构域。具有紧密和粘附连接，但最近也报道了其细胞质和核定位。一项全基因组关联研究揭示了 Magi1 基因位点突变与炎症性肠病和银屑病关节炎 EC 炎症在调节中的重要作用。这些疾病的表型和严重程度，在临床上也与加速相关动脉粥样硬化（AS）和心血管疾病的风险增加，已得到初步证实。通过数据，我们发现 MAGI1 翻译后修饰 (PTM) 在调节 EC 中的关键作用 MAGI1 S741 磷酸化导致 Rap1 和大肿瘤的激活。抑制子 1 (LATS1)（但不是 Yes 相关蛋白 [YAP] 磷酸化，这是一个典型途径 MAGI1 去 SUMO 化导致 MAGI1 和 p90RSK 共易位至在细胞核中，它们上调炎症基因的表达。 MAGI1 PTM 的动态调节（磷酸化和去 SUMO 化）导致胞质 Rap1 和非典型的 LATS 信号激活，以及胞质和核中的 p90RSK MAGI1。隔室在调节 EC 炎症和细胞凋亡以及随后的动脉粥样硬化形成中发挥着关键作用。目标 1 将确定 MAGI1 S741 磷酸化促进 EC 炎症的机制目标 2 将确定 MAGI1 去 SUMO 化在核易位和促进 EC 中的作用。在目标 3 中，我们将确定 MAGI1 和 LATS1/2 在加速 AS 中的作用。 MAGI1 PTM 包括磷酸化和去 SUMO 化诱导的 EC 炎症，是新颖且突出的确定这种包含 PDZ 结构域的分子和 p90RSK 如何协调调节 EC 的重要性该项目的长期目标是确定 MAGI1 磷酸化的作用。和（去）SUMO化在调节MAGI1亚细胞定位和MAGI1依赖性信号传导中的作用阐明 MAGI1 诱导 EC 炎症和细胞凋亡并促进这将使我们更深入地了解导致不良结果的基本信号传导。 AS 相关的心血管疾病。

项目成果

期刊论文数量（18）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Endothelial senescence is induced by phosphorylation and nuclear export of telomeric repeat binding factor 2-interacting protein.

内皮衰老是由端粒重复结合因子 2 相互作用蛋白的磷酸化和核输出诱导的。

DOI：
发表时间：
2019-05-02
期刊：
影响因子：
8
作者：
Kotla, Sivareddy;Vu, Hang Thi;Ko, Kyung Ae;Wang, Yin;Imanishi, Masaki;Heo, Kyung;Fujii, Yuka;Thomas, Tamlyn N;Gi, Young Jin;Mazhar, Hira;Paez;Shin, Ji;Tao, Yunting;Giancursio, Carolyn J;Medina, Jan Lm;Taunton, Jack
通讯作者：
Taunton, Jack

SARS-CoV-2 Mediated Endothelial Dysfunction: The Potential Role of Chronic Oxidative Stress.

SARS-CoV-2 介导的内皮功能障碍：慢性氧化应激的潜在作用。