Function and mechanism of a novel SUMO protease

描述（由申请人提供）：Sumoylation是小泛素样修饰物（SUMO）在细胞蛋白上的共价附着，已成为调节蛋白质活性、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机制。与泛素化一样，sumoylation是一种动态的、可逆的翻译后修饰，由sumoylation酶和SUMO蛋白酶（也称为去sumoylation酶）的相反作用控制。Sumoylation在许多细胞过程的调控中起着关键作用，从转录调控和DNA修复到蛋白质运输、线粒体动力学和细胞凋亡。sumoylation失调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summoylation对人类健康和疾病的重要性，但我们对summoylation /去summoylation机制成分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的SUMO蛋白酶及其在细胞防御氧化应激和凋亡中的信号作用。拟议的研究结果将促进我们对所有真核细胞中SUMO信号传导的基本机制的认识，并为理解和治疗涉及SUMO酰化失调的各种人类疾病提供分子基础。

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.