Function and mechanism of a novel SUMO protease

新型SUMO蛋白酶的功能和机制

• 批准号: 8588945
• 负责人: LIAN LI
• 金额: $ 29.64万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-12-01 至 2016-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8588945
• 关键词: Alzheimer' s Disease; Apoptosis; Biochemical; Biological; Cell physiology; Cells; Complex; Cysteine; Cysteine Protease; Cytoprotection; DNA Repair; Data; Development; Diabetes Mellitus; Disease; Enzymes; Eukaryotic Cell; Family; Functional disorder; Genetic; Goals; Health; Heart Diseases; Human; Huntington Disease; Impairment; Investigation; Knowledge; Link; Malignant Neoplasms; Methionine; Mitochondria; Mitochondrial Proteins; Molecular; Mus; Mutation; Nerve Degeneration; Neurodegenerative Disorders; Nuclear Proteins; Oxidation-Reduction; Oxidative Stress; Parkinson Disease; Pathogenesis; Peptide Hydrolases; Phosphorylation; Physiological; Physiology; Play; Post-Translational Protein Processing; Process; Proteins; Proteomics; RNA Binding; Reaction; Regulation; Research; Role; Signal Pathway; Signal Transduction; Stroke; Structure-Activity Relationship; Test Result; Testing; Therapeutic; Transcriptional Regulation; Ubiquitin; Ubiquitination; Up-Regulation; age related; base; early onset; follow-up; human disease; male; novel; oxidation; protein protein interaction; protein transport; public health relevance; response

DESCRIPTION (provided by applicant): Sumoylation, the covalent attachment of small ubiquitin-like modifier (SUMO) to cellular proteins, has emerged as an important signaling mechanism for regulating protein activity, stability/degradation, subcellular localization, and protein-protein interaction. Like ubiquitination, sumoylation is a dynamic and reversible post-translational modification that is controlled by opposing actions of sumoylating enzymes and SUMO proteases (also known as desumoylating enzymes). Sumoylation plays a critical role in regulation of numerous cellular processes, from transcriptional regulation and DNA repair to protein trafficking, mitochondrial dynamics, and apoptosis. Dysregulated sumoylation has been implicated in a variety of human diseases, including cancer, diabetes, heart disease, and neurodegenerative disorders such as Alzheimer and Parkinson diseases. Despite increasing evidence supporting the importance of sumoylation to human health and disease, our knowledge about the sumoylation/desumoylation machinery components and their cellular functions is limited. In this project, the applicant's team will use a combination of biochemical, proteomic, cell biological, and mouse genetic approaches to study a novel SUMO protease and its signaling role in cellular defense against oxidative stress and apoptosis. The results of the proposed studies should advance our knowledge of the fundamental mechanisms governing SUMO signaling in all eukaryotic cells and provide a molecular basis for understanding and treating a diverse array of human diseases that involve dysregulated sumoylation.

描述（由申请人提供）：SUMO化，即小泛素样修饰物（SUMO）与细胞蛋白的共价连接，已成为调节蛋白活性、稳定性/降解、亚细胞定位和蛋白质-蛋白质相互作用的重要信号传导机制。与泛素化一样，小泛素化是一种动态的可逆的翻译后修饰，由小泛素化酶和SUMO蛋白酶（也称为去小泛素化酶）的相反作用控制。类小泛素化在许多细胞过程的调节中起关键作用，从转录调节和DNA修复到蛋白质运输、线粒体动力学和凋亡。失调的类小泛素化与多种人类疾病有关，包括癌症、糖尿病、心脏病和神经退行性疾病如阿尔茨海默病和帕金森病。尽管越来越多的证据支持类小泛素化对人类健康和疾病的重要性，但我们对类小泛素化/去类小泛素化机制组件及其细胞功能的了解有限。在这个项目中，申请人的团队将使用生物化学，蛋白质组学，细胞生物学和小鼠遗传学方法的组合来研究一种新型SUMO蛋白酶及其在细胞防御氧化应激和细胞凋亡中的信号作用。拟议的研究结果应该推进我们的知识的基本机制，在所有真核细胞SUMO信号转导，并提供了一个分子基础，了解和治疗各种各样的人类疾病，涉及失调sumoylation。