Rahman Mohammad M, Stuchlick Olga, El-Karim Enas G, Stuart Ryan, Kipreos Edward T, Wells Lance
Department of Genetics, University of Georgia, Athens, 30602, USA.
Aging (Albany NY). 2010 Oct;2(10):678-90. doi: 10.18632/aging.100208.
O-linked-β-N-acetylglucosamine (O-GlcNAc) modification is a regulatory, nuclear and cytoplasmic post-translational glycosylation of proteins associated with age-related diseases such as Alzheimer's, Parkinson's, and type II diabetes. Global elevation of O-GlcNAc levels on intracellular proteins can induce insulin resistance, the hallmark of type II diabetes, in mammalian systems. InC. elegans, attenuation of the insulin-like signal transduction pathway increases adult lifespan of the nematode. We demonstrate that the O-GlcNAc cycling enzymes OGT and OGA, which add and remove O-GlcNAc respectively, modulate lifespan in C. elegans. Median adult lifespan is increased in an oga-1 deletion strain while median adult life span is decreased upon ogt-1 deletion. The O-GlcNAc-mediated effect on nematode lifespan is dependent on the FoxO transcription factor DAF-16. DAF-16 is a key factor in the insulin-like signal transduction pathway to regulate reproductive development, lifespan, stress tolerance, and dauer formation in C. elegans. Our data indicates that O-GlcNAc cycling selectively influences only a subset of DAF-16 mediated phenotypes, including lifespan and oxidative stress resistance. We performed an affinity purification of O-GlcNAc-modified proteins and observed that a high percentage of these proteins are regulated by insulin signaling and/or impact insulin pathway functional outcomes, suggesting that the O-GlcNAc modification may control downstream effectors to modulate insulin pathway mediated cellular processes.
O-连接的β-N-乙酰葡糖胺（O-GlcNAc）修饰是一种与阿尔茨海默病、帕金森病和II型糖尿病等年龄相关疾病相关的蛋白质的调节性、核质翻译后糖基化修饰。细胞内蛋白质上O-GlcNAc水平的整体升高可在哺乳动物系统中诱导胰岛素抵抗，这是II型糖尿病的标志。在秀丽隐杆线虫中，胰岛素样信号转导途径的减弱会延长线虫的成虫寿命。我们证明，分别添加和去除O-GlcNAc的O-GlcNAc循环酶OGT和OGA可调节秀丽隐杆线虫的寿命。oga-1缺失菌株的成虫平均寿命增加，而ogt-1缺失后成虫平均寿命缩短。O-GlcNAc对线虫寿命的影响依赖于FoxO转录因子DAF-16。DAF-16是胰岛素样信号转导途径中调节秀丽隐杆线虫生殖发育、寿命、应激耐受性和 dauer 形成的关键因子。我们的数据表明，O-GlcNAc循环仅选择性地影响DAF-16介导的一部分表型，包括寿命和抗氧化应激能力。我们对O-GlcNAc修饰的蛋白质进行了亲和纯化，发现这些蛋白质中有很大一部分受胰岛素信号调节和/或影响胰岛素途径的功能结果，这表明O-GlcNAc修饰可能控制下游效应器来调节胰岛素途径介导的细胞过程。
