Phosphoinositide signalling links O-GlcNAc transferase to insulin resistance

Xiaoyong Yang, Pat P. Ongusaha, Philip D. Miles, Joyce C. Havstad, Fengxue Zhang, W. Venus So, Jeffrey E. Kudlow, Robert H. Michell, Jerrold M. Olefsky, Seth J. Field and Ronald M. Evans ()
Additional contact information
Xiaoyong Yang: Howard Hughes Medical Institute and Gene Expression Laboratory, The Salk Institute for Biological Studies, La Jolla, California 92037, USA
Pat P. Ongusaha: Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts 02129, USA
Philip D. Miles: University of California, San Diego, La Jolla, California 92093, USA
Joyce C. Havstad: Howard Hughes Medical Institute and Gene Expression Laboratory, The Salk Institute for Biological Studies, La Jolla, California 92037, USA
Fengxue Zhang: University of Alabama, Birmingham, Alabama 35294, USA
W. Venus So: Roche Group Research Information, Hoffmann-La Roche, Inc., Nutley, New Jersey 07110, USA
Jeffrey E. Kudlow: University of Alabama, Birmingham, Alabama 35294, USA
Robert H. Michell: School of Biosciences, University of Birmingham
Jerrold M. Olefsky: University of California, San Diego, La Jolla, California 92093, USA
Seth J. Field: University of California, San Diego, La Jolla, California 92093, USA
Ronald M. Evans: Howard Hughes Medical Institute and Gene Expression Laboratory, The Salk Institute for Biological Studies, La Jolla, California 92037, USA

Nature, 2008, vol. 451, issue 7181, 964-969

Abstract: Abstract Glucose flux through the hexosamine biosynthetic pathway leads to the post-translational modification of cytoplasmic and nuclear proteins by O-linked β-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.

Date: 2008
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DOI: 10.1038/nature06668

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