生物谷报道：O位N-乙酰葡萄糖胺(O-GlcNAc)对核蛋白和胞质蛋白的修饰正在成为很多细胞过程的一个关键调控因子。人们怀疑，它们所扮演的一个角色是充当营养传感器，与通过氨基己糖生物合成通道的葡萄糖流量相关。对O-GlcNAc相应于葡萄糖流量所起作用所做的一项研究显示，在O-GlcNAc转移酶(OGT)上有一个新型类脂结合点：在胰岛素刺激下，有一种类脂与OGT结合，将其吸收进胞质膜中。然后，OGT用糖来“装饰”胰岛素信号通道蛋白，抑制它们的活性，阻滞胰岛素反应。OGT在小鼠肝脏中的过度表达引起胰岛素抗性和血脂异常。因此，胰岛素信号通道的异常O-GlcNAc修饰有助于胰岛素抗性、肥胖症和2型糖尿病的形成。（科学时报）
英文原文：
Nature 451, 964-969 (21 February 2008) | doi:10.1038/nature06668; Received 6 October 2007; Accepted 7 January 2008
Phosphoinositide signalling links O-GlcNAc transferase to insulin resistance
Xiaoyong Yang1, Pat P. Ongusaha2, Philip D. Miles3, Joyce C. Havstad1, Fengxue Zhang4, W. Venus So5, Jeffrey E. Kudlow4, Robert H. Michell6, Jerrold M. Olefsky3, Seth J. Field3 & Ronald M. Evans1
Howard Hughes Medical Institute and Gene Expression Laboratory, The Salk Institute for Biological Studies, La Jolla, California 92037, USA
Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts 02129, USA
Department of Medicine, University of California, San Diego, La Jolla, California 92093, USA
Department of Medicine, University of Alabama, Birmingham, Alabama 35294, USA
Roche Group Research Information, Hoffmann-La Roche, Inc., Nutley, New Jersey 07110, USA
School of Biosciences, University of Birmingham, Birmingham B15 2TT, UK
Correspondence to: Ronald M. Evans1 Correspondence and requests for materials should be addressed to R.M.E. (Email: evans@salk.edu).
Abstract
Glucose flux through the hexosamine biosynthetic pathway leads to the post-translational modification of cytoplasmic and nuclear proteins by O-linked -N-acetylglucosamine (O-GlcNAc). This tandem system serves as a nutrient sensor to couple systemic metabolic status to cellular regulation of signal transduction, transcription, and protein degradation. Here we show that O-GlcNAc transferase (OGT) harbours a previously unrecognized type of phosphoinositide-binding domain. After induction with insulin, phosphatidylinositol 3,4,5-trisphosphate recruits OGT from the nucleus to the plasma membrane, where the enzyme catalyses dynamic modification of the insulin signalling pathway by O-GlcNAc. This results in the alteration in phosphorylation of key signalling molecules and the attenuation of insulin signal transduction. Hepatic overexpression of OGT impairs the expression of insulin-responsive genes and causes insulin resistance and dyslipidaemia. These findings identify a molecular mechanism by which nutritional cues regulate insulin signalling through O-GlcNAc, and underscore the contribution of this modification to the aetiology of insulin resistance and type 2 diabetes.
