Dissecting the roles of ubiquitin in translation control

剖析泛素在翻译控制中的作用

• 批准号: 10439835
• 负责人: Gustavo M Silva
• 金额: $ 39.44万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10439835
• 关键词: Aging; Award; Biological Process; Cell physiology; Cells; Cessation of life; Collaborations; Deubiquitination; Disease; Enzymes; Eukaryota; Failure; Future; Gene Expression; Goals; Individual; Interdisciplinary Study; Lead; Link; Mission; Modification; Molecular; Molecular Computations; National Institute of General Medical Sciences; Neurodegenerative Disorders; Oxidative Stress; Oxides; Pathway interactions; Polyubiquitin; Post-Translational Protein Processing; Process; Production; Protein Biosynthesis; Proteins; Proteomics; Reaction; Regulation; Research; Resistance; Ribosomes; Role; Site; Source; Stress; Translations; Ubiquitin; Ubiquitination; United States National Institutes of Health; Variant; Work; fighting; molecular marker; programs; protein degradation; protein expression; response; three dimensional structure; tool; tumor progression

Project Summary The long-term goal of the Silva Lab is to determine the molecular mechanism by which protein ubiquitination controls protein synthesis and cellular survival in response to oxidative stress. Oxidizers are constantly produced by a variety of endogenous and exogenous sources and translation is an essential cellular process that must be finely reprogrammed when cells are challenged with oxidizers. Failure to reprogram protein expression, accumulation of damaged proteins, and inadequate management of oxidizers are the underlying causes of a variety of neurodegenerative diseases, tumor progression, and the process of aging. Understanding and modulating stress defense pathways, such as translation, would provide new tools to promote healthier lives and fight diseases. In eukaryotes, a variety of defense pathways is regulated by ubiquitin. Protein ubiquitination is a prevalent post-translational modification initially characterized as the molecular marker for protein degradation. We have recently identified a new role for a poly-ubiquitin variant (K63-linked) in the regulation of protein synthesis during oxidative stress. Using molecular and proteomics approaches, our lab showed that ribosomes are the main target of K63 ubiquitin, K63 ubiquitin is essential for cellular viability, and that specific enzymes are involved in ribosomal ubiquitination and deubiquitination reactions. However, there is still a limited understanding of how K63 ubiquitin impacts ribosome activity and the protein expression program. This MIRA award will support the Silva Lab program of research, which will use a combination of large-scale, molecular, and computational approaches to understand each one of the steps necessary for regulation of translation by K63 ubiquitin. These steps include recognition of ribosome by ubiquitin enzymes, modification of individual ubiquitin sites, alteration of ribosome 3D structure, reconfiguration of translation landscape, and determination of the fate of ubiquitinated ribosomes. Defining the molecular mechanisms regulating such a fundamental biological process as protein synthesis is key to enhancing cellular resistance to stress and reshaping our understanding of gene expression control. This work will lead to an established and independent research program, future NIH research awards, expanded collaboration network, and interdisciplinary research within the NIGMS mission.

项目摘要 席尔瓦实验室的长期目标是确定蛋白质泛素化的分子机制， 控制蛋白质合成和细胞存活以响应氧化应激。不断产生氧化剂 通过各种内源性和外源性来源和翻译是一个必不可少的细胞过程， 当细胞受到氧化剂的挑战时，无法重新编程蛋白质表达， 受损蛋白质的积累和氧化剂的管理不足是导致 各种神经退行性疾病、肿瘤进展和衰老过程。理解和 调节压力防御途径，如翻译，将提供新的工具，以促进更健康的生活， 对抗疾病。在真核生物中，多种防御途径受泛素调节。蛋白质泛素化是一种 普遍的翻译后修饰最初被表征为蛋白质降解的分子标记。 我们最近发现了多聚泛素变体（K63-linked）在蛋白质表达调控中的新作用。 在氧化应激期间合成。利用分子和蛋白质组学方法，我们的实验室表明， 是K63泛素的主要靶点，K63泛素对细胞活力至关重要，并且特定的酶是 参与核糖体泛素化和去泛素化反应。但是，目前还存在认识上的局限 K63泛素如何影响核糖体活性和蛋白质表达程序。该MIRA奖将支持 席尔瓦实验室的研究计划，这将使用大规模的，分子和计算的组合， 了解K63泛素调控翻译所需的每一个步骤的方法。这些 步骤包括通过泛素酶识别核糖体，修饰单个泛素位点，改变 核糖体3D结构，翻译景观的重新配置，以及决定泛素化的命运 核糖体定义调节蛋白质等基本生物过程的分子机制 合成是增强细胞抗应激能力和重塑我们对基因表达理解的关键 控制这项工作将导致一个既定的和独立的研究计划，未来的NIH研究奖， 在NIGMS使命内扩大合作网络和跨学科研究。