Deciphering the ubiquitin code in stress signaling and membrane trafficking

破译应激信号传导和膜运输中的泛素代码

• 批准号: 10557826
• 负责人: Jason A MacGurn
• 金额: $ 39.63万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-01 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10557826
• 关键词: Amino Acids; Binding Proteins; Biochemical; Biology; Cell physiology; Cells; Cellular Stress; Code; Elements; Enzymes; Eukaryotic Cell; Family; Genetic; Glucose Transporter; Human; Investigation; Length; Malignant Neoplasms; Membrane; Modification; Nerve Degeneration; Pathway interactions; Peptides; Phosphorylation; Phosphotransferases; Polymers; Positioning Attribute; Post-Translational Protein Processing; Proteins; Proteomics; Quality Control; Regulation; Research; SLC2A1 gene; Signal Transduction; Stress; Syndrome; Ubiquitin; Work; Writing; Yeasts; biological adaptation to stress; blood glucose regulation; cancer type; human disease; insight; protein degradation; protein protein interaction; proteostasis; response; therapeutic target; trafficking

Project Summary Ubiquitin is a 76 amino acid peptide that can be covalently conjugated to substrates to alter protein fate in diverse ways, regulating protein degradation, trafficking, subcellular localization and protein-protein interactions. Given its versatility, ubiquitin regulates many fundamental cellular processes, and its dysregulation is associated with many human diseases ranging from neurodegeneration to cancer. Ubiquitin networks include conjugating and deconjugating enzymes as well as effector pathways comprised of ubiquitin binding proteins that direct the fate of ubiquitin-modified substrates. All of these elements work together to “write”, “read”, and “edit” the ubiquitin code – which ultimately consists of ubiquitin polymers of different lengths and topologies that determine which effector pathways are engaged. Here, we describe two main research directions that will result in a deeper understanding of the ubiquitin code and how it regulates diverse cellular functions, including stress signaling and membrane trafficking. The first research direction will address how phosphorylation of ubiquitin at the Ser57 position regulates stress responses in yeast and human cells. The proposed studies will build on our recent discovery of a small group of Ser57 ubiquitin kinases conserved from yeast to humans and will include genetic, biochemical, and proteomic approaches. Specifically, we will determine how these kinases and Ser57 phosphorylation of ubiquitin contribute to the cellular stress response, and we will address how ubiquitin phosphorylation alters its interaction profile and engagement with effector pathways. This research will contribute transformative new insights into the biology of ubiquitin and proteostasis. The second research direction will address how human glucose transporters are regulated by ubiquitin modification and endocytic trafficking. Glucose transporters of the GLUT family are key regulators of cellular glucose homeostasis, and yet regulation of their trafficking and quality control remain poorly characterized. Here, we describe lines of investigation based on our recent findings that GLUT1 endocytic trafficking is regulated by specific ubiquitin modifications. These studies have important implications for cellular glucose homeostasis and human diseases including GLUT1 Deficiency Syndrome and many types of cancer. Together, these research directions will result in a deeper understanding of the ubiquitin code, membrane trafficking, and stress responses in eukaryotic cells.

项目摘要 泛素是一种76个氨基酸肽，可以共价连接到底物以改变蛋白质命运 潜水方式，控制蛋白质降解，运输，亚细胞定位和蛋白质蛋白质 互动。鉴于其多功能性，泛素调节了许多基本的细胞过程及其 失调与从神经退行性变化到癌症的许多人类疾病有关。泛素 网络包括共轭和解共轭酶以及泛素的效应途径 指导泛素修饰底物的命运的结合蛋白。所有这些元素共同起作用 “写”，“读”和“编辑”泛素代码 - 最终由不同长度的泛素聚合物组成 以及确定哪种效应途径的拓扑结构。在这里，我们描述了两项主要研究 方向将使对泛素代码及其如何调节细胞的泛素代码有更深入的了解 功能，包括应力信号传导和膜运输。第一个研究方向将解决如何 泛素在Ser57位置的磷酸化调节酵母和人类细胞中的应力反应。这 拟议的研究将基于我们最近发现的一小部分SER57泛素激酶 酵母对人类，包括遗传，生化和蛋白质组学方法。具体来说，我们会的 确定泛素的这些激酶和Ser57磷酸化如何有助于细胞应激反应， 我们将解决泛素磷酸化如何改变其相互作用曲线和与效应器的互动 途径。这项研究将为泛素和生物学的变革性新见解和 蛋白毒酸。第二个研究方向将解决人类葡萄糖转运蛋白如何受到 泛素修饰和内吞运输。 Glut家族的葡萄糖转运蛋白是关键调节剂 细胞葡萄糖稳态，但对其贩运和质量控制的调节仍然很差 特征。在这里，我们根据我们最近发现的GLUT1内吞作用的调查线 贩运受特定的泛素修饰调节。这些研究对细胞具有重要意义 葡萄糖稳态和人类疾病，包括GLUT1缺乏综合征和许多类型的癌症。 这些研究方向共同使对泛素代码，膜有更深入的了解 贩运和真核细胞中的压力反应。