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Phosphoinositide signalling links O-GlcNAc transferase to insulin resistance

Nature volume 451, pages 964–969 (2008)Cite this article

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.

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Figure 1: OGT interacts with phosphoinositides.
Figure 2: Phosphoinositide signalling mediates OGT translocation.
Figure 3: O -GlcNAc dynamically regulates insulin signalling pathway.
Figure 4: Hepatic overexpression of OGT produces insulin resistance.
Figure 5: OGT overexpression causes phosphoinositide-dependent perturbation of insulin signalling.

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Acknowledgements

We thank T. Hunter, B. Burgering, J. Yuan and O. Gozani for providing reagents; R. Shaw for advice; R. Shaw, S. Dove and H. Cho for critical reading of the manuscript; Z. Wu for help with statistical analysis; M. Nelson and K. Kawamura for technical assistance; and L. Ong and S. Ganley for administrative assistance. X.Y. is the recipient of a Ruth L. Kirschstein National Research Service Award Individual Fellowship. R.M.E. is an Investigator of the Howard Hughes Medical Institute at the Salk Institute and March of Dimes Chair in Molecular and Developmental Biology. R.M.E. is supported by grants from the Howard Hughes Medical Institute and the NIH (National Institute of Diabetes and Digestive and Kidney Diseases, and Nuclear Receptor Signaling Atlas). J.M.O. is supported by NIH grants and a University of California Discovery BioStar grant with matching funds from Pfizer Incorporated. S.J.F. is supported by grants from the Burroughs Wellcome Fund, the V Foundation, and the NIH.

Author Contributions X.Y. conceived the project, designed and performed most of the experiments. P.P.O. and S.J.F. participated in protein–lipid binding and cell imaging experiments. P.D.M. performed hyperinsulinaemic–euglycaemic glucose clamp studies. J.C.H. assisted in biochemical and animal experiments. F.Z. performed OGT activity assays. W.V.S. performed bioinformatic analyses. J.M.O., R.H.M., J.E.K. and S.J.F. provided intellectual input and technical expertise. R.M.E. supervised the project. X.Y. and R.M.E. wrote the manuscript.

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Authors and Affiliations

  1. Howard Hughes Medical Institute and Gene Expression Laboratory, The Salk Institute for Biological Studies, La Jolla, California 92037, USA,

    Xiaoyong Yang, Joyce C. Havstad & Ronald M. Evans

  2. Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts 02129, USA,

    Pat P. Ongusaha

  3. Department of Medicine, University of California, San Diego, La Jolla, California 92093, USA,

    Philip D. Miles, Jerrold M. Olefsky & Seth J. Field

  4. Department of Medicine, University of Alabama, Birmingham, Alabama 35294, USA,

    Fengxue Zhang & Jeffrey E. Kudlow

  5. Roche Group Research Information, Hoffmann-La Roche, Inc., Nutley, New Jersey 07110, USA,

    W. Venus So

  6. School of Biosciences, University of Birmingham, Birmingham B15 2TT, UK

    Robert H. Michell

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Yang, X., Ongusaha, P., Miles, P. et al. Phosphoinositide signalling links O-GlcNAc transferase to insulin resistance. Nature 451, 964–969 (2008). https://doi.org/10.1038/nature06668

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