Tools for investigating O-GlcNAc in Signaling and other Fundamental Biological Pathways.
Tools for investigating O-GlcNAc in Signaling and other Fundamental Biological Pathways.
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DOI：
10.1016/j.jbc.2023.105615
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发表时间：
2023-12
期刊：
影响因子：
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通讯作者：
Zachary M. Nelson;Garry D. Leonard;C. Fehl
中科院分区：
文献类型：
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作者：
Zachary M. Nelson;Garry D. Leonard;C. Fehl
细胞通过用 O-连接的 N-乙酰氨基葡萄糖 (O-GlcNAc) 糖修饰细胞内蛋白质，不断微调信号通路蛋白，以匹配局部环境中的营养和应激水平，这是细胞生存和生长的重要过程。这些单糖修饰的小尺寸对功能测定提出了挑战，但化学和生物学界共同创建了一系列精密工具来研究这些动态糖。本综述介绍了 O-GlcNAc 影响信号转导通路蛋白的主要主题，包括 G 蛋白偶联受体、生长因子信号转导、丝裂原激活蛋白激酶 (MAPK) 通路、脂质传感和细胞因子信号转导通路。在此过程中，我们详细描述了已开发和应用的关键化学生物学工具，以确定 O-GlcNAc 在这些途径中的特定作用。这些工具包括代谢标记、O-GlcNAc 增强 RNA 适体、荧光生物传感器、邻近标记工具、纳米抗体靶向工具、O-GlcNAc 循环抑制剂、光激活系统、化学酶标记和营养报告分析。这种信号通路荟萃分析的一个新特征是不同信号系统中 O-GlcNAc 修饰之间复杂的相互作用，强调了 O-GlcNAc 在调节细胞过程中的重要性。我们强调了 O-GlcNAc 在信号传导中的重要性以及化学和生化工具在阐明不同的糖生物学调节机制中的作用。总的来说，我们的领域已经确定了探索 O-GlcNAc 在生物学中的作用的有效策略。与此同时，这项对我们尚不了解的内容的调查为该领域使用这些强大的化学工具探索信号传导和其他主要生物途径中的跨途径 O-GlcNAc 相互作用提供了清晰的路线图。
Cells continuously fine-tune signaling pathway proteins to match nutrient and stress levels in their local environment by modifying intracellular proteins with O-linked N-acetylglucosamine (O-GlcNAc) sugars, an essential process for cell survival and growth. The small size of these monosaccharide modifications poses a challenge for functional determination, but the chemistry and biology communities have together created a collection of precision tools to study these dynamic sugars. This review presents the major themes by which O-GlcNAc influences signaling pathway proteins, including G-protein coupled receptors, growth factor signaling, mitogen-activated protein kinase (MAPK) pathways, lipid sensing, and cytokine signaling pathways. Along the way, we describe in detail key chemical biology tools that have been developed and applied to determine specific O-GlcNAc roles in these pathways. These tools include metabolic labeling, O-GlcNAc-enhancing RNA aptamers, fluorescent biosensors, proximity labeling tools, nanobody targeting tools, O-GlcNAc cycling inhibitors, light-activated systems, chemoenzymatic labeling, and nutrient reporter assays. An emergent feature of this signaling pathway meta-analysis is the intricate interplay between O-GlcNAc modifications across different signaling systems, underscoring the importance of O-GlcNAc in regulating cellular processes. We highlight the significance of O-GlcNAc in signaling and the role of chemical and biochemical tools in unraveling distinct glycobiological regulatory mechanisms. Collectively, our field has determined effective strategies to probe O-GlcNAc roles in biology. At the same time, this survey of what we do not yet know presents a clear roadmap for the field to use these powerful chemical tools to explore cross-pathway O-GlcNAc interactions in signaling and other major biological pathways.