Global analysis of the selectivity of proteostatic pathways

抑蛋白途径选择性的整体分析

• 批准号: 10164911
• 负责人: SINA GHAEMMAGHAMI
• 金额: $ 38.32万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10164911
• 关键词: Cells; Client; Goals; Homeostasis; Impairment; Methionine; Molecular; Neurodegenerative Disorders; Organelles; Oxidative Stress; Oxides; Pathologic; Pathway interactions; Play; Prevalence; Prions; Proteins; Proteome; Proteomics; Regulation; Research; Role; Stress; System; Tissues; base; experimental study; insight; methionine sulfoxide reductase; novel; oxidation; programs; protein degradation; proteostasis; proteotoxicity; repaired

Summary Within a cell, a number of pathways contribute to the repair and clearance of proteins and are required for maintaining protein homeostasis (proteostasis). A common feature of proteostatic pathways is their ability to act on a range of client proteins that vary based on cellular and environmental conditions. The molecular mechanisms of the selectivity of many proteostatic pathways remain incompletely understood. The overall goal of our research program is to investigate the mechanisms that determine the selectivity of proteostatic pathways by conducting functional analyses on proteome-wide scales. As a first step towards this long-term objective, we have focused on investigating the global selectivities of the macroautophagy pathway and methionine sulfoxide reductases. Macroautophagy can selectively target specific proteins and organelles for lysosomic degradation. Using novel proteomic approaches, we have identified subsets of proteins that rely on macroautophagy for their constitutive turnover. We have also shown that selective autophagic degradation plays a major role in maintaining protein homeostasis in quiescent cells and that alterations in autophagic flux is a pathologic feature of prion infected cells. Our future research will focus on understanding the molecular mechanisms of the differential selectivity of basal macroautophagy and investigating the prevalence and regulation of selective macroautophagy in quiescent and prion infected cells. The methionine sulfoxide reductase (Msr) system is an important repair pathway for oxidized methionine residues in proteins. To facilitate global analyses of the selectivity of Msrs, we have developed novel proteomic approaches for accurate quantitation of methionine oxidation on proteome-wide scales. Using these approaches, we plan to investigate the extent of methionine oxidation in proteomes of cells and tissues that are deficient in specific Msrs under normal and oxidative stress conditions. Together, the proposed experiments will provide insights into the mechanisms of client selection by macroautophagy and Msr pathways. Our studies will also examine the role of these two pathways in mitigating protein damage that occurs under specific proteotoxic stress conditions.

概括 在细胞内，许多途径有助于修复和清除蛋白质和 是维持蛋白质稳态（蛋白质稳态）所必需的。一个共同的特点是 蛋白抑制途径是它们作用于一系列客户蛋白的能力，这些客户蛋白根据不同的情况而变化。 细胞和环境条件。许多选择性的分子机制 蛋白质抑制途径仍不完全清楚。我们研究的总体目标 计划的目的是研究决定蛋白静态选择性的机制 通过在蛋白质组范围内进行功能分析来探索途径。作为第一步 为了实现这一长期目标，我们重点研究了全球选择性 巨自噬途径和蛋氨酸亚砜还原酶。 巨自噬可以选择性地靶向特定蛋白质和细胞器进行溶酶体吞噬 降解。使用新的蛋白质组学方法，我们已经确定了蛋白质的子集 依靠巨自噬来实现其组成周转。我们还表明，选择性 自噬降解在维持静态蛋白质稳态中发挥着重要作用 细胞自噬流的改变是朊病毒感染细胞的病理特征。 我们未来的研究将集中于了解其分子机制 基础巨自噬的差异选择性并调查其患病率和 静止和朊病毒感染细胞中选择性巨自噬的调节。 蛋氨酸亚砜还原酶（Msr）系统是重要的修复途径 蛋白质中的氧化蛋氨酸残基。促进选择性的全球分析 女士们，我们开发了新的蛋白质组学方法来准确定量 蛋白质组范围内的蛋氨酸氧化。使用这些方法，我们计划 研究细胞和组织蛋白质组中蛋氨酸氧化的程度 在正常和氧化应激条件下缺乏特定的 Msrs。 总之，所提出的实验将提供对客户机制的见解 通过巨自噬和 Msr 途径进行选择。我们的研究还将探讨 这两种途径可以减轻特定蛋白质毒性下发生的蛋白质损伤 压力条件。