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 在一个单元中，许多途径有助于蛋白质的修复和清除 维持蛋白质稳态（蛋白抑制）所必需。一个共同特征的 蛋白质静态途径是他们在一系列客户蛋白上作用的能力，这些蛋白质因 细胞和环境条件。许多选择性的分子机制 蛋白静态途径仍然不完全理解。我们研究的总体目标 程序是研究确定蛋白抑制性选择性的机制 通过对全蛋白质组尺度进行功能分析来进行途径。作为第一步 为了实现这一长期目标，我们专注于调查全球选择性 大自藻的途径和甲硫氨酸还原酶。 大噬菌可以有选择地靶向溶酶体的特定蛋白质和细胞器 降解。使用新型的蛋白质组学方法，我们已经确定了蛋白质的子集 依靠大型噬菌体进行本构的营业额。我们还表明了选择性 自噬降解在维持蛋白质稳态中起着重要作用 细胞和自噬通量的改变是prion感染细胞的病理特征。 我们未来的研究将集中于理解分子机制 基础大噬菌的差异选择性并研究了患病率和 调节静止和prion感染细胞中选择性大噬细胞的调节。 蛋氨酸亚氧化亚氧化物还原酶（MSR）系统是重要的修复途径 蛋白质中氧化的蛋氨酸残基。促进全球分析的选择性 MSR，我们开发了新颖的蛋白质组学方法，以精确定量 蛋氨酸在全蛋白质组尺度上的氧化。使用这些方法，我们计划 研究细胞和组织蛋白质蛋白氧化的程度 在正常和氧化应激条件下缺乏特定的MSR。 拟议的实验将共同提供对客户机制的见解 大型自噬和MSR途径的选择。我们的研究还将研究 这两种途径减轻特定蛋白质毒性下发生的蛋白质损伤 压力条件。