Novel Posttranslational Modifications in Adipose Biology

脂肪生物学中的新型翻译后修饰

基本信息

批准号：
10780577
负责人：
Weiqin Chen
金额：
$ 15.4万
依托单位：
AUGUSTA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-05-01 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10780577
关键词：
Acceleration Adipocytes Adipose tissue Adult Atrophic Biochemical Biological Biological Process Biology Biotinylation Body fat Brown Fat CUL3 gene Cardiometabolic Disease Cullin Proteins Data Disease Endocrine Glands Energy Metabolism Enzymes Equilibrium Family member Fatty acid glycerol esters Functional disorder Genetic Transcription Health Heart failure Homeostasis Impairment Inflammation Inflammatory Insulin Resistance Knowledge Ligase Link Lipodystrophy Maintenance Malignant Neoplasms Mediating Metabolic Metabolic Diseases Methaqualone Mitochondria Mitochondrial Proteins Modification Molecular Mus Nuclear Obesity Organism Oxidation-Reduction Pathologic Phenocopy Phosphotransferases Post-Translational Protein Processing Process Production Proteins Proteome Proteomics Regulation Research Respiration Role Signal Transduction Site System Testing Thermogenesis Ubiquitin Ubiquitin Like Proteins Ubiquitination Up-Regulation energy balance improved insight kinase inhibitor mitochondrial dysfunction novel pharmacologic ubiquitin ligase ubiquitin-protein ligase

项目摘要

Project Summary Metabolic health depends on the maintenance of normal mass and function of adipose tissue (AT). Accumulation of excess body fat or pathological loss of AT is associated with insulin resistance and cardiometabolic diseases. White AT (WAT) and brown AT (BAT) act together to maintain a balance between fat accumulation and energy expenditure. Upstream players that regulate WAT and BAT maintenance remain less characterized. Ubiquitin (Ub) and Ub-like proteins modify diverse protein substrates and expand the functional diversity of the proteome. However, the functional role of NEDD8, a novel Ub-like protein that has the highest homology with Ub, remains poorly understood in the adipose tissue. Neddylation covalently attaches NEDD8 to target proteins via NEDD8-specific E1-E2-E3 enzymes. Induced adipose deletion of NAE1 (a regulatory subunit of the NEDD8 E1 enzyme) in mice resulted in loss of adipose tissue potentially through mitochondrial dysfunction and inflammation. Pharmacological inhibition of neddylation promoted mitochondrial ROS production and impaired mitochondrial function in mature adipocytes. Interestingly, AT-specific loss of CUL3 (a bona fide neddylation target) largely phenocopied neddylation deficiency-induced AT loss, and neddylation dominantly targets CUL3 to modulate mitochondrial function and adipocyte turnover. In BAT, neddylation deficiency causes BAT atrophy and activation of non-canonical NF-κB signaling. These compelling preliminary data form the basis of our central hypothesis that neddylation is required for mature white and brown adipose tissue maintenance through regulation of CUL3-mediated mitochondrial function and/or non-canonical NF-κB pro-inflammatory signaling. Aim 1 will establish the significance and identify the proteome of neddylation in regulating mitochondrial dysfunction, adipose tissue remodeling and thus energy balance and adaptive thermogenesis. Aim 2 will dissect the molecular basis by which neddylation targets a novel mitochondrial targeted CUL3 E3 Ub ligase to mediate adipocyte mitochondrial activity and turnover thus energy balance. Aim 3 will elucidate a newly identified neddylation target in mediating non-canonical NF-κB signaling to accelerate brown adipocyte inflammation and turnover. Our proposed study will provide the most in-depth analysis of neddylation as a hitherto novel post-translational modification essential for both mature white and brown adipose tissue maintenance. We expect that new findings from this proposal will provide novel insights into our understanding of the pathophysiology of adipose tissue and its implications on obesity/ lipodystrophy and its associated metabolic disorders.

项目概要代谢健康取决于脂肪组织（AT）正常质量和功能的维持。体内过多脂肪的积累或 AT 的病理性损失与胰岛素抵抗和白色 AT (WAT) 和棕色 AT (BAT) 共同作用以维持脂肪之间的平衡。监管 WAT 和 BAT 维护的上游参与者仍然较少。泛素 (Ub) 和 Ub 样蛋白修饰不同的蛋白质底物并扩展功能。然而，NEDD8（一种新型 Ub 样蛋白）的功能作用最高。 Neddylation 与 Ub 的同源性在脂肪组织中仍知之甚少。通过 NEDD8 特异性 E1-E2-E3 酶诱导 NAE1（调节亚基）的脂肪缺失。 NEDD8 E1 酶）在小鼠体内可能通过线粒体功能障碍导致脂肪组织损失 neddylation 的药理抑制促进线粒体 ROS 的产生和炎症。成熟脂肪细胞中线粒体功能受损。 neddylation 目标）很大程度上是表型复制的 neddylation 缺陷引起的 AT 丢失，并且 neddylation 占主导地位靶向 CUL3 调节线粒体功能和脂肪细胞更新在 BAT 中，neddylation 缺陷会导致。 BAT 萎缩和非规范 NF-κB 信号传导的激活这些令人信服的初步数据构成了基础。我们的中心假设是成熟的白色和棕色脂肪组织需要neddylation 通过调节 CUL3 介导的线粒体功能和/或非经典 NF-κB 来维持目标 1 将确定 neddylation 的重要性并鉴定其蛋白质组。调节线粒体功能障碍、脂肪组织重塑，从而调节能量平衡和适应性目标 2 将剖析 neddylation 靶向新型线粒体的分子基础。靶向 CUL3 E3 Ub 连接酶介导脂肪细胞线粒体活性和周转，从而实现能量平衡。 3 将阐明新发现的 neddylation 靶标，该靶标可介导非经典 NF-κB 信号传导，以加速我们提出的研究将为棕色脂肪细胞炎症和周转提供最深入的分析。 neddylation 作为迄今为止新颖的翻译后修饰，对于成熟的白色和棕色脂肪都至关重要我们期望该提案的新发现将为我们提供新的见解。了解脂肪组织的病理生理学及其对肥胖/脂肪营养不良及其影响相关的代谢紊乱。