From the Complex Carbohydrate Research Center and Biochemistry and Molecular Biology Department, University of Georgia, Athens, Georgia 30602
J Biol Chem. 2019 Feb 15;294(7):2211-2231. doi: 10.1074/jbc.AW119.003226. Epub 2019 Jan 9.
In the early 1980s, while using purified glycosyltransferases to probe glycan structures on surfaces of living cells in the murine immune system, we discovered a novel form of serine/threonine protein glycosylation (-linked β-GlcNAc; -GlcNAc) that occurs on thousands of proteins within the nucleus, cytoplasm, and mitochondria. Prior to this discovery, it was dogma that protein glycosylation was restricted to the luminal compartments of the secretory pathway and on extracellular domains of membrane and secretory proteins. Work in the last 3 decades from several laboratories has shown that -GlcNAc cycling serves as a nutrient sensor to regulate signaling, transcription, mitochondrial activity, and cytoskeletal functions. -GlcNAc also has extensive cross-talk with phosphorylation, not only at the same or proximal sites on polypeptides, but also by regulating each other's enzymes that catalyze cycling of the modifications. -GlcNAc is generally not elongated or modified. It cycles on and off polypeptides in a time scale similar to phosphorylation, and both the enzyme that adds -GlcNAc, the -GlcNAc transferase (OGT), and the enzyme that removes -GlcNAc, -GlcNAcase (OGA), are highly conserved from to humans. Both -GlcNAc cycling enzymes are essential in mammals and plants. Due to -GlcNAc's fundamental roles as a nutrient and stress sensor, it plays an important role in the etiologies of chronic diseases of aging, including diabetes, cancer, and neurodegenerative disease. This review will present an overview of our current understanding of -GlcNAc's regulation, functions, and roles in chronic diseases of aging.
在 20 世纪 80 年代早期，我们使用纯化的糖基转移酶来探测小鼠免疫系统中活细胞表面的聚糖结构，在此过程中发现了一种新型丝氨酸/苏氨酸蛋白糖基化（β-GlcNAc 连接的 -GlcNAc；-GlcNAc）形式，这种糖基化形式存在于细胞核、细胞质和线粒体中的数千种蛋白质中。在此发现之前，有一种教条认为蛋白质糖基化仅限于分泌途径的腔室和膜及分泌蛋白的细胞外结构域。过去 30 年来自几个实验室的工作表明，-GlcNAc 循环作为一种营养传感器，可调节信号转导、转录、线粒体活性和细胞骨架功能。-GlcNAc 还与磷酸化广泛交叉对话，不仅在多肽的相同或邻近部位，还通过调节催化修饰循环的彼此的酶来进行。-GlcNAc 通常不会延长或修饰。它在与磷酸化相似的时间尺度上在多肽上进行加和去修饰循环，并且添加 -GlcNAc 的酶（-GlcNAc 转移酶，OGT）和去除 -GlcNAc 的酶（-GlcNAcase，OGA）在从到人类的范围内高度保守。在哺乳动物和植物中，-GlcNAc 循环酶都是必需的。由于 -GlcNAc 作为营养和应激传感器的基本作用，它在衰老相关慢性疾病（包括糖尿病、癌症和神经退行性疾病）的发病机制中起着重要作用。这篇综述将概述我们目前对 -GlcNAc 调节、功能及其在衰老相关慢性疾病中的作用的理解。
