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

• 批准号: 9284797
• 负责人: Shu-Bing Qian
• 金额: $ 31.17万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-05-12 至 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9284797
• 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

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.

项目摘要 翻译控制在应激条件下维持蛋白质稳态中起着关键作用，因为它允许 蛋白质水平的即时和选择性变化。翻译控制领域一个长期存在的问题 是细胞mRNA能够进行帽非依赖性翻译的机制。细胞如何 然而，对应激时mRNA翻译的协调差异模式仍然知之甚少。这个目标 项目是研究动态O-GlcNAc酰化反应的压力，并了解其在帽， 独立的mRNA翻译。已经提出O-GlcNAc调节多种细胞过程，包括 转录和细胞信号通路。我们的初步结果表明，O-GlcNAc酰化开关 eIF 4G 1从帽依赖性到帽非依赖性启动的功能。我们进一步发现了一种 非帽依赖性mRNA翻译中O-GlcNAc化、ABCF 1和mRNA甲基化之间的联系。 这些发现导致了中心假设，即应激诱导的eIF 4G 1的O-GlcNAc修饰 通过重塑起始前复合物的形成，识别甲基化， mRNA，并促进帽非依赖性翻译。为了检验这一假设，提出了以下目标： 1)表征eIF 4G 1在O-GlcNAc酰化后的功能开关; 2）定义ABCF 1在O-GlcNAc酰化中的作用。 GlcNAc信号传导; 3）剖析mRNA甲基化和O-GlcNAc信号传导之间的网络。这些目标 是彼此独立的，但在其翻译控制中的O-GlcNAc信号传导的中心焦点上是统一的 压力反应。通过将创新方法整合到翻译调控的基础研究中， 这些研究将为mRNA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， 细胞内稳态和压力适应。