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O-GlcNAc Signaling in Translational Control of Stress Response

O-GlcNAc 信号传导在应激反应转化控制中的作用

基本信息

批准号：
9908101
负责人：
Shu-Bing Qian
金额：
$ 31.4万
依托单位：
CORNELL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-05-12 至 2022-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9908101
关键词：
Binding Biochemical Biological Assay CRISPR/Cas technology Cell Survival Cell physiology Cells Complex Development Diabetes Mellitus Disease Ensure Gene Expression Gene Expression Regulation Genes Genetic Transcription Genetic Translation Goals Growth Heat-Shock Proteins 70 Heat-Shock Response Homeostasis Internal Ribosome Entry Site Knowledge Licensing Malignant Neoplasms Mass Spectrum Analysis Mediating Messenger RNA Methods Methylation Methyltransferase Modification Molecular Nature Organism Pattern Peptide Initiation Factors Physiological Play Process Production Protein Biosynthesis Proteins Reader Reporting Research Ribosomes Role Scaffolding Protein Signal Pathway Signal Transduction Stimulus Stress Testing Trans-Activators Translation Initiation Translation Process Translational Regulation Translations biological adaptation to stress combat design genetic approach genome-wide human disease innovation insight mutant novel novel therapeutic intervention proteostasis response sugar tool

项目摘要

PROJECT SUMMARY Translational control plays a critical role in maintaining protein homeostasis under stress conditions as it allows immediate and selective changes in protein levels. A long-standing question in the field of translational control is the mechanism through which cellular mRNAs are able to undergo cap-independent translation. How cells orchestrate differential modes of mRNA translation upon stress remains poorly understood. The goal of this project is to investigate dynamic O-GlcNAcylation in response to stress and understand its role in cap- independent mRNA translation. O-GlcNAc has been proposed to regulate diverse cellular processes, including transcription and cell signaling pathways. Our preliminary results have indicated that O-GlcNAcylation switches the function of eIF4G1 from cap-dependent to cap-independent initiation. We further uncovered a mechanistic linkage between O-GlcNAcylation, ABCF1, and mRNA methylation in cap-independent mRNA translation. These findings led to the central hypothesis that stress-induced O-GlcNAc modification of eIF4G1 licenses cap-independent mRNA translation by remodeling pre-initiation complex formation, recognizing methylated mRNA, and facilitating cap-independent translation. To test this hypothesis, the following Aims are proposed: 1) Characterize the functional switch of eIF4G1 upon O-GlcNAcylation; 2) Define the role of ABCF1 in O- GlcNAc signaling; 3) Dissect the network between mRNA methylation and O-GlcNAc signaling. These Aims are independent of one another but unified in their central focus on O-GlcNAc signaling in translational control of stress response. By integrating innovative approaches into fundamental studies of translational regulation, the proposed studies will open up new avenues of research in the field of mRNA translation. The mechanistic insights we gain from this study will provide paradigms for better understanding of translational control in cellular homeostasis and stress adaptation.

项目总结在应激条件下，翻译控制在维持蛋白质动态平衡方面起着关键作用。蛋白质水平的即刻和选择性变化。翻译控制领域中的一个长期存在的问题是细胞内mRNAs能够进行帽子非依赖性翻译的机制。显示单元格在应激状态下协调不同的信使核糖核酸翻译模式仍然知之甚少。这样做的目的是该项目是研究动态O-GlcN酰化对压力的响应，并了解其在CAP-2中的作用。独立的信使核糖核酸翻译。O-GlcNAc已被提出用来调节不同的细胞过程，包括转录和细胞信号通路。我们的初步结果表明，O-GlcN酰化开关 EIF4G1的功能从帽依赖到帽非依赖的启动。我们进一步揭示了一种机械论 O-GlcN酰化、ABCF1和mRNA甲基化在帽非依赖性的mRNA翻译中的联系。这些发现导致了一个中心假设，即应激诱导eIF4G1许可证的O-GlcNAc修饰通过重塑预起始复合体的形成，识别甲基化，实现帽非依赖性的mRNA翻译 MRNA，并促进大小写无关的翻译。为了验证这一假设，提出了以下目标： 1)鉴定eIF4G1在O-GlcN酰化过程中的功能开关；2)确定ABCF1在O-GlcN酰化过程中的作用。 3)分析了O-GlcNAc信号与mRNA甲基化之间的网络。这些目标都是相互独立的，但在翻译控制中集中在O-GlcNAc信号上是统一的压力反应。通过将创新方法整合到翻译监管的基础研究中，这些研究将为信使翻译领域的研究开辟新的途径。机械论我们从这项研究中获得的见解将为更好地理解翻译控制提供范例。细胞动态平衡和压力适应。