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Phosphoinositide signalling links O-GlcNAc transferase to insulin resistance

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Listed:
  • 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)

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.

Suggested Citation

  • 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 & Ronald M. Evans, 2008. "Phosphoinositide signalling links O-GlcNAc transferase to insulin resistance," Nature, Nature, vol. 451(7181), pages 964-969, February.
    • Handle: RePEc:nat:nature:v:451:y:2008:i:7181:d:10.1038_nature06668
    DOI: 10.1038/nature06668
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    Cited by:

    1. Thulaciga Yoganathan & Mailyn Perez-Liva & Daniel Balvay & Morgane Gall & Alice Lallemand & Anais Certain & Gwennhael Autret & Yasmine Mokrani & François Guillonneau & Johanna Bruce & Vincent Nguyen &, 2023. "Acute stress induces long-term metabolic, functional, and structural remodeling of the heart," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    2. Shahzina Kanwal & Yann Fardini & Patrick Pagesy & Thierry N’Tumba-Byn & Cécile Pierre-Eugène & Elodie Masson & Cornelia Hampe & Tarik Issad, 2013. "O-GlcNAcylation-Inducing Treatments Inhibit Estrogen Receptor α Expression and Confer Resistance to 4-OH-Tamoxifen in Human Breast Cancer-Derived MCF-7 Cells," PLOS ONE, Public Library of Science, vol. 8(7), pages 1-1, July.

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