生物谷報(bào)道：O位N-乙酰葡萄糖胺(O-GlcNAc)對(duì)核蛋白和胞質(zhì)蛋白的修飾正在成為很多細(xì)胞過(guò)程的一個(gè)關(guān)鍵調(diào)控因子,。人們懷疑,，它們所扮演的一個(gè)角色是充當(dāng)營(yíng)養(yǎng)傳感器，與通過(guò)氨基己糖生物合成通道的葡萄糖流量相關(guān),。對(duì)O-GlcNAc相應(yīng)于葡萄糖流量所起作用所做的一項(xiàng)研究顯示,，在O-GlcNAc轉(zhuǎn)移酶(OGT)上有一個(gè)新型類脂結(jié)合點(diǎn)：在胰島素刺激下，有一種類脂與OGT結(jié)合,，將其吸收進(jìn)胞質(zhì)膜中,。然后，OGT用糖來(lái)“裝飾”胰島素信號(hào)通道蛋白,，抑制它們的活性,，阻滯胰島素反應(yīng)。OGT在小鼠肝臟中的過(guò)度表達(dá)引起胰島素抗性和血脂異常,。因此,，胰島素信號(hào)通道的異常O-GlcNAc修飾有助于胰島素抗性、肥胖癥和2型糖尿病的形成,。（科學(xué)時(shí)報(bào)）
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: [email protected]).
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.
