Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Protein O-GlcNAcylation: emerging mechanisms and functions

Nature Reviews Molecular Cell Biology volume 18, pages 452–465 (2017)Cite this article

Subjects

This article has been updated

Key Points

  • O-GlcNAcylation is a nutrient- and stress-responsive post-translational modification (PTM) that involves the attachment of O-linked N-acetylglucosamine moieties to Ser and Thr residues of cytoplasmic, nuclear and mitochondrial proteins. A single pair of enzymes — O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA) — controls the dynamic cycling of this PTM.

  • Potential mechanisms that enable a single OGT enzyme to recognize hundreds of protein substrates include substrate-specific interactions with the tetratricopeptide repeat (TPR) domain of OGT and context-dependent recruitment of OGT to its substrates by a hierarchy of conserved adaptor proteins. Furthermore, in response to cellular stress, O-GlcNAcylation may occur nonspecifically in unstructured regions of unfolded proteins in order to block their aggregation and degradation and facilitate their refolding.

  • O-GlcNAcylation is involved in the spatiotemporal regulation of diverse cellular processes, which include transcription, epigenetic modifications and cell signalling dynamics. O-GlcNAcylation is highly dynamic and often transient, but the mechanisms underlying the temporal control of O-GlcNAc signalling are largely unknown.

  • Nutrient availability regulates cellular O-GlcNAcylation levels not only by determining the abundance of the donor substrate uridine diphosphate GlcNAc (UDP-GlcNAc) but also by modulating the levels of OGT, OGA and their respective adaptor proteins and substrates. Hormones such as insulin, glucagon and ghrelin are secreted in response to systemic metabolic changes and modulate O-GlcNAc signalling in specific cell types and tissues to regulate key response pathways that help maintain metabolic homeostasis.

  • Cellular O-GlcNAcylation levels may be maintained within an 'optimal zone' by a 'buffering system' that is generated by mutual regulation of OGT and OGA at the transcriptional and post-translational levels. Maintenance of O-GlcNAc homeostasis is essential for optimal cellular function, and disruption of the cellular O-GlcNAcylation 'buffer' may contribute to the pathogenesis of various human diseases.

  • O-GlcNAcylation can be viewed as the essential 'grease and glue' of the cell: it acts as a 'grease' by coating target proteins (folded or unfolded, mature or nascent) and preventing unwanted protein aggregation or modification; it also acts as a 'glue' by modulating protein–protein interactions in time and space in response to internal and external cues, thereby affecting the functions of various proteins in the cell.

Abstract

O-GlcNAcylation — the attachment of O-linked N-acetylglucosamine (O-GlcNAc) moieties to cytoplasmic, nuclear and mitochondrial proteins — is a post-translational modification that regulates fundamental cellular processes in metazoans. A single pair of enzymes — O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA) — controls the dynamic cycling of this protein modification in a nutrient- and stress-responsive manner. Recent years have seen remarkable advances in our understanding of O-GlcNAcylation at levels that range from structural and molecular biology to cell signalling and gene regulation to physiology and disease. New mechanisms and functions of O-GlcNAcylation that are emerging from these recent developments enable us to begin constructing a unified conceptual framework through which the significance of this modification in cellular and organismal physiology can be understood.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Nutrient flux through the hexosamine biosynthetic pathway regulates protein O-GlcNAcylation.
Figure 2: Potential mechanisms of substrate recognition by O-GlcNAc transferase.
Figure 3: Functions of O-GlcNAcylation in time and space.
Figure 4: Nutritional and hormonal regulation of O-GlcNAc signalling.
Figure 5: Maintenance of O-GlcNAc homeostasis by mutual regulation of O-GlcNAc transferase and O-GlcNAcase.

Similar content being viewed by others

Change history

  • 26 May 2017

    In the version of this article initially published online, several instances of the definition of O-GlcNAcylation have been corrected. In addition, a number of formatting mistakes have been addressed. These errors have been corrected in the HTML, print and PDF versions of the article.

References

  1. Hart, G. W., Housley, M. P. & Slawson, C. Cycling of O-linked β-N-acetylglucosamine on nucleocytoplasmic proteins. Nature 446, 1017–1022 (2007).

    Article  CAS  PubMed  Google Scholar 

  2. Hart, G. W., Slawson, C., Ramirez-Correa, G. & Lagerlof, O. Cross talk between O-GlcNAcylation and phosphorylation: roles in signaling, transcription, and chronic disease. Annu. Rev. Biochem. 80, 825–858 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Yi, W. et al. Phosphofructokinase 1 glycosylation regulates cell growth and metabolism. Science 337, 975–980 (2012). Demonstrates that hypoxia-induced O -GlcNAcylation of a glycolytic enzyme promotes metabolic reprogramming in cancer.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Slawson, C. & Hart, G. W. O-GlcNAc signalling: implications for cancer cell biology. Nat. Rev. Cancer 11, 678–684 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Yang, X. et al. Phosphoinositide signalling links O-GlcNAc transferase to insulin resistance. Nature 451, 964–969 (2008). Demonstrates that phosphoinositide-mediated recruitment of OGT from the cytoplasm to the plasma membrane leads to attenuation of insulin signal transduction.

    Article  CAS  PubMed  Google Scholar 

  6. Ruan, H. B., Singh, J. P., Li, M. D., Wu, J. & Yang, X. Cracking the O-GlcNAc code in metabolism. Trends Endocrinol. Metab. 24, 301–309 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Yuzwa, S. A. et al. Increasing O-GlcNAc slows neurodegeneration and stabilizes tau against aggregation. Nat. Chem. Biol. 8, 393–399 (2012).

    Article  CAS  PubMed  Google Scholar 

  8. Zhu, Y., Shan, X., Yuzwa, S. A. & Vocadlo, D. J. The emerging link between O-GlcNAc and Alzheimer disease. J. Biol. Chem. 289, 34472–34481 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  9. Bond, M. R. & Hanover, J. A. O-GlcNAc cycling: a link between metabolism and chronic disease. Annu. Rev. Nutr. 33, 205–229 (2013).

    Article  CAS  PubMed  Google Scholar 

  10. Hanover, J. A., Krause, M. W. & Love, D. C. Bittersweet memories: linking metabolism to epigenetics through O-GlcNAcylation. Nat. Rev. Mol. Cell Biol. 13, 312–321 (2012).

    Article  CAS  PubMed  Google Scholar 

  11. Bond, M. R. & Hanover, J. A. A little sugar goes a long way: the cell biology of O-GlcNAc. J. Cell Biol. 208, 869–880 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Levine, Z. G. & Walker, S. The biochemistry of O-GlcNAc transferase: which functions make it essential in mammalian cells? Annu. Rev. Biochem. 85, 631–657 (2016).

    Article  CAS  PubMed  Google Scholar 

  13. Lazarus, M. B., Nam, Y., Jiang, J., Sliz, P. & Walker, S. Structure of human O-GlcNAc transferase and its complex with a peptide substrate. Nature 469, 564–567 (2011). The first report to describe the complete crystal structure of human OGT.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Pathak, S. et al. The active site of O-GlcNAc transferase imposes constraints on substrate sequence. Nat. Struct. Mol. Biol. 22, 744–750 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Janetzko, J. & Walker, S. The making of a sweet modification: structure and function of O-GlcNAc transferase. J. Biol. Chem. 289, 34424–34432 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. Yang, X., Zhang, F. & Kudlow, J. E. Recruitment of O-GlcNAc transferase to promoters by corepressor mSin3A: coupling protein O-GlcNAcylation to transcriptional repression. Cell 110, 69–80 (2002). Demonstrates that O -GlcNAcylation and histone deacetylation act in parallel to promote gene silencing.

    Article  CAS  PubMed  Google Scholar 

  17. Myers, S. A., Panning, B. & Burlingame, A. L. Polycomb repressive complex 2 is necessary for the normal site-specific O-GlcNAc distribution in mouse embryonic stem cells. Proc. Natl Acad. Sci. USA 108, 9490–9495 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Chen, Q., Chen, Y., Bian, C., Fujiki, R. & Yu, X. TET2 promotes histone O-GlcNAcylation during gene transcription. Nature 493, 561–564 (2013). The first report to describe the physical and functional interaction of OGT with TET proteins.

    Article  CAS  PubMed  Google Scholar 

  19. Zhang, Q. et al. Differential regulation of the ten-eleven translocation (TET) family of dioxygenases by O-linked β-N-acetylglucosamine transferase (OGT). J. Biol. Chem. 289, 5986–5996 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Lazarus, M. B. et al. HCF-1 is cleaved in the active site of O-GlcNAc transferase. Science 342, 1235–1239 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Jinek, M. et al. The superhelical TPR-repeat domain of O-linked GlcNAc transferase exhibits structural similarities to importin α. Nat. Struct. Mol. Biol. 11, 1001–1007 (2004).

    Article  CAS  PubMed  Google Scholar 

  22. Love, D. C., Kochan, J., Cathey, R. L., Shin, S. H. & Hanover, J. A. Mitochondrial and nucleocytoplasmic targeting of O-linked GlcNAc transferase. J. Cell Sci. 116, 647–654 (2003).

    Article  CAS  PubMed  Google Scholar 

  23. Lazarus, B. D., Love, D. C. & Hanover, J. A. Recombinant O-GlcNAc transferase isoforms: identification of O-GlcNAcase, yes tyrosine kinase, and tau as isoform-specific substrates. Glycobiology 16, 415–421 (2006).

    Article  CAS  PubMed  Google Scholar 

  24. Trapannone, R., Mariappa, D., Ferenbach, A. T. & van Aalten, D. M. Nucleocytoplasmic human O-GlcNAc transferase is sufficient for O-GlcNAcylation of mitochondrial proteins. Biochem. J. 473, 1693–1702 (2016).

    Article  CAS  PubMed  Google Scholar 

  25. Cheung, W. D. & Hart, G. W. AMP-activated protein kinase and p38 MAPK activate O-GlcNAcylation of neuronal proteins during glucose deprivation. J. Biol. Chem. 283, 13009–13020 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Ruan, H. B. et al. O-GlcNAc transferase/host cell factor C1 complex regulates gluconeogenesis by modulating PGC-1α stability. Cell Metab. 16, 226–237 (2012). Demonstrates that HCF1 recruits OGT to PGC1α to promote gluconeogenesis during fasting.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Whisenhunt, T. R. et al. Disrupting the enzyme complex regulating O-GlcNAcylation blocks signaling and development. Glycobiology 16, 551–563 (2006).

    Article  CAS  PubMed  Google Scholar 

  28. Vucic, D., Dixit, V. M. & Wertz, I. E. Ubiquitylation in apoptosis: a post-translational modification at the edge of life and death. Nat. Rev. Mol. Cell Biol. 12, 439–452 (2011).

    Article  CAS  PubMed  Google Scholar 

  29. Li, B. & Kohler, J. J. Glycosylation of the nuclear pore. Traffic 15, 347–361 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Zhu, Y. et al. O-GlcNAc occurs cotranslationally to stabilize nascent polypeptide chains. Nat. Chem. Biol. 11, 319–325 (2015). The first report to describe co-translational O -GlcNAcylation of nascent polypeptide chains.

    Article  CAS  PubMed  Google Scholar 

  31. Fardini, Y. et al. Regulatory O-GlcNAcylation sites on FoxO1 are yet to be identified. Biochem. Biophys. Res. Commun. 462, 151–158 (2015).

    Article  CAS  PubMed  Google Scholar 

  32. Eijkelenboom, A. & Burgering, B. M. FOXOs: signalling integrators for homeostasis maintenance. Nat. Rev. Mol. Cell Biol. 14, 83–97 (2013).

    Article  CAS  PubMed  Google Scholar 

  33. Zachara, N. E. et al. Dynamic O-GlcNAc modification of nucleocytoplasmic proteins in response to stress. A survival response of mammalian cells. J. Biol. Chem. 279, 30133–30142 (2004).

    Article  CAS  PubMed  Google Scholar 

  34. Hetz, C. The unfolded protein response: controlling cell fate decisions under ER stress and beyond. Nat. Rev. Mol. Cell Biol. 13, 89–102 (2012).

    Article  CAS  PubMed  Google Scholar 

  35. Wang, Z. V. et al. Spliced X-box binding protein 1 couples the unfolded protein response to hexosamine biosynthetic pathway. Cell 156, 1179–1192 (2014). Demonstrates that transcriptional activation of the HBP by the UPR is a generalizable response to cellular stress.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Marotta, N. P. et al. O-GlcNAc modification blocks the aggregation and toxicity of the protein α-synuclein associated with Parkinson's disease. Nat. Chem. 7, 913–920 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Zhang, F. et al. O-GlcNAc modification is an endogenous inhibitor of the proteasome. Cell 115, 715–725 (2003).

    Article  CAS  PubMed  Google Scholar 

  38. Li, M. D. et al. O-GlcNAc signaling entrains the circadian clock by inhibiting BMAL1/CLOCK ubiquitination. Cell Metab. 17, 303–310 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Ruan, H. B., Nie, Y. & Yang, X. Regulation of protein degradation by O-GlcNAcylation: crosstalk with ubiquitination. Mol. Cell Proteomics 12, 3489–3497 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Guinez, C., Lemoine, J., Michalski, J. C. & Lefebvre, T. 70-kDa-heat shock protein presents an adjustable lectinic activity towards O-linked N-acetylglucosamine. Biochem. Biophys. Res. Commun. 319, 21–26 (2004).

    Article  CAS  PubMed  Google Scholar 

  41. Guinez, C., Losfeld, M. E., Cacan, R., Michalski, J. C. & Lefebvre, T. Modulation of HSP70 GlcNAc-directed lectin activity by glucose availability and utilization. Glycobiology 16, 22–28 (2006).

    Article  CAS  PubMed  Google Scholar 

  42. Guinez, C. et al. Hsp70-GlcNAc-binding activity is released by stress, proteasome inhibition, and protein misfolding. Biochem. Biophys. Res. Commun. 361, 414–420 (2007).

    Article  CAS  PubMed  Google Scholar 

  43. Alonso, J., Schimpl, M. & van Aalten, D. M. O-GlcNAcase: promiscuous hexosaminidase or key regulator of O-GlcNAc signaling? J. Biol. Chem. 289, 34433–34439 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  44. Li, B., Li, H., Lei, L. & Jiang, J. Structures of human O-GlcNAcase and its complexes reveal a new substrate recognition mode. Nat. Struct. Mol. Biol. 24, 362–369 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Elsen, N. L. et al. Insights into activity and inhibition from the crystal structure of human O-GlcNAcase. Nat. Chem. Biol. http://dx.doi.org/10.1038/nchembio.2357 (2017).

  46. Roth, C. et al. Structural and functional insight into human O-GlcNAcase. Nat. Chem. Biol. http://dx.doi.org/10.1038/nchembio.2358 (2017).

  47. Dennis, R. J. et al. Structure and mechanism of a bacterial β-glucosaminidase having O-GlcNAcase activity. Nat. Struct. Mol. Biol. 13, 365–371 (2006).

    Article  CAS  PubMed  Google Scholar 

  48. Rao, F. V. et al. Structural insights into the mechanism and inhibition of eukaryotic O-GlcNAc hydrolysis. EMBO J. 25, 1569–1578 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Schimpl, M., Borodkin, V. S., Gray, L. J. & van Aalten, D. M. Synergy of peptide and sugar in O-GlcNAcase substrate recognition. Chem. Biol. 19, 173–178 (2012). Demonstrates that substrate recognition by OGA is mediated by its interactions with the peptide backbone and sugar moiety.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Martin, J. C., Fadda, E., Ito, K. & Woods, R. J. Defining the structural origin of the substrate sequence independence of O-GlcNAcase using a combination of molecular docking and dynamics simulation. Glycobiology 24, 85–96 (2014).

    Article  CAS  PubMed  Google Scholar 

  51. Kreppel, L. K., Blomberg, M. A. & Hart, G. W. Dynamic glycosylation of nuclear and cytosolic proteins. Cloning and characterization of a unique O-GlcNAc transferase with multiple tetratricopeptide repeats. J. Biol. Chem. 272, 9308–9315 (1997). The first report to describe the cloning of rat OGT.

    Article  CAS  PubMed  Google Scholar 

  52. Lubas, W. A., Frank, D. W., Krause, M. & Hanover, J. A. O-Linked GlcNAc transferase is a conserved nucleocytoplasmic protein containing tetratricopeptide repeats. J. Biol. Chem. 272, 9316–9324 (1997). The first report to describe the cloning of C. elegans ogt-1 and human OGT.

    Article  CAS  PubMed  Google Scholar 

  53. Wells, L. et al. Dynamic O-glycosylation of nuclear and cytosolic proteins: further characterization of the nucleocytoplasmic β-N-acetylglucosaminidase, O-GlcNAcase. J. Biol. Chem. 277, 1755–1761 (2002).

    Article  PubMed  Google Scholar 

  54. Jackson, S. P. & Tjian, R. O-Glycosylation of eukaryotic transcription factors: implications for mechanisms of transcriptional regulation. Cell 55, 125–133 (1988).

    Article  CAS  PubMed  Google Scholar 

  55. Golks, A., Tran, T. T., Goetschy, J. F. & Guerini, D. Requirement for O-linked N-acetylglucosaminyltransferase in lymphocytes activation. EMBO J. 26, 4368–4379 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Dentin, R. et al. Hepatic glucose sensing via the CREB coactivator CRTC2. Science 319, 1402–1405 (2008).

    Article  CAS  PubMed  Google Scholar 

  57. Housley, M. P. et al. O-GlcNAc regulates FoxO activation in response to glucose. J. Biol. Chem. 283, 16283–16292 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Yang, W. H. et al. NFκB activation is associated with its O-GlcNAcylation state under hyperglycemic conditions. Proc. Natl Acad. Sci. USA 105, 17345–17350 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Ramakrishnan, P. et al. Activation of the transcriptional function of the NF-κB protein c-Rel by O-GlcNAc glycosylation. Sci. Signal. 6, ra75 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  60. Li, M. D. et al. O-GlcNAc transferase is involved in glucocorticoid receptor-mediated transrepression. J. Biol. Chem. 287, 12904–12912 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Majumdar, G. et al. Insulin dynamically regulates calmodulin gene expression by sequential O-glycosylation and phosphorylation of sp1 and its subcellular compartmentalization in liver cells. J. Biol. Chem. 281, 3642–3650 (2006).

    Article  CAS  PubMed  Google Scholar 

  62. Yang, X. et al. O-Linkage of N-acetylglucosamine to Sp1 activation domain inhibits its transcriptional capability. Proc. Natl Acad. Sci. USA 98, 6611–6616 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Han, I. & Kudlow, J. E. Reduced O glycosylation of Sp1 is associated with increased proteasome susceptibility. Mol. Cell. Biol. 17, 2550–2558 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Kelly, W. G., Dahmus, M. E. & Hart, G. W. RNA polymerase II is a glycoprotein. Modification of the COOH-terminal domain by O-GlcNAc. J. Biol. Chem. 268, 10416–10424 (1993).

    CAS  PubMed  Google Scholar 

  65. Lewis, B. A., Burlingame, A. L. & Myers, S. A. Human RNA polymerase II promoter recruitment in vitro is regulated by O-linked N-acetylglucosaminyltransferase (OGT). J. Biol. Chem. 291, 14056–14061 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Lewis, B. A. & Hanover, J. A. O-GlcNAc and the epigenetic regulation of gene expression. J. Biol. Chem. 289, 34440–34448 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  67. Dehennaut, V., Leprince, D. & Lefebvre, T. O-GlcNAcylation, an epigenetic mark. focus on the histone code, TET family proteins, and polycomb group proteins. Front. Endocrinol. (Lausanne) 5, 155 (2014).

    Article  Google Scholar 

  68. Singh, J. P., Zhang, K., Wu, J. & Yang, X. O-GlcNAc signaling in cancer metabolism and epigenetics. Cancer Lett. 356, 244–250 (2015).

    Article  CAS  PubMed  Google Scholar 

  69. Daou, S. et al. Crosstalk between O-GlcNAcylation and proteolytic cleavage regulates the host cell factor-1 maturation pathway. Proc. Natl Acad. Sci. USA 108, 2747–2752 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Scheuermann, J. C. et al. Histone H2A deubiquitinase activity of the Polycomb repressive complex PR-DUB. Nature 465, 243–247 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Chu, C. S. et al. O-GlcNAcylation regulates EZH2 protein stability and function. Proc. Natl Acad. Sci. USA 111, 1355–1360 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Gambetta, M. C., Oktaba, K. & Muller, J. Essential role of the glycosyltransferase sxc/Ogt in polycomb repression. Science 325, 93–96 (2009).

    Article  CAS  PubMed  Google Scholar 

  73. Rasmussen, K. D. & Helin, K. Role of TET enzymes in DNA methylation, development, and cancer. Genes Dev. 30, 733–750 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Shi, F. T. et al. Ten-eleven translocation 1 (Tet1) is regulated by O-linked N-acetylglucosamine transferase (Ogt) for target gene repression in mouse embryonic stem cells. J. Biol. Chem. 288, 20776–20784 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Vella, P. et al. Tet proteins connect the O-linked N-acetylglucosamine transferase Ogt to chromatin in embryonic stem cells. Mol. Cell 49, 645–656 (2013).

    Article  CAS  PubMed  Google Scholar 

  76. Deplus, R. et al. TET2 and TET3 regulate GlcNAcylation and H3K4 methylation through OGT and SET1/COMPASS. EMBO J. 32, 645–655 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Zhang, K., Yin, R. & Yang, X. O-GlcNAc: a bittersweet switch in liver. Front. Endocrinol. (Lausanne) 5, 221 (2014).

    Google Scholar 

  78. Vosseller, K., Wells, L., Lane, M. D. & Hart, G. W. Elevated nucleocytoplasmic glycosylation by O-GlcNAc results in insulin resistance associated with defects in Akt activation in 3T3-L1 adipocytes. Proc. Natl Acad. Sci. USA 99, 5313–5318 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Soesanto, Y. A. et al. Regulation of Akt signaling by O-GlcNAc in euglycemia. Am. J. Physiol. Endocrinol. Metab. 295, E974–E980 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Shi, J. et al. O-GlcNAcylation regulates ischemia-induced neuronal apoptosis through AKT signaling. Sci. Rep. 5, 14500 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Bridges, D. & Saltiel, A. R. Phosphoinositides: key modulators of energy metabolism. Biochim. Biophys. Acta 1851, 857–866 (2015).

    Article  CAS  PubMed  Google Scholar 

  82. Whelan, S. A., Dias, W. B., Thiruneelakantapillai, L., Lane, M. D. & Hart, G. W. Regulation of insulin receptor substrate 1 (IRS-1)/AKT kinase-mediated insulin signaling by O-linked β-N-acetylglucosamine in 3T3-L1 adipocytes. J. Biol. Chem. 285, 5204–5211 (2010).

    Article  CAS  PubMed  Google Scholar 

  83. Macauley, M. S. et al. Inhibition of O-GlcNAcase using a potent and cell-permeable inhibitor does not induce insulin resistance in 3T3-L1 adipocytes. Chem. Biol. 17, 937–948 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Taylor, R. P. et al. Glucose deprivation stimulates O-GlcNAc modification of proteins through up- regulation of O-linked N-acetylglucosaminyltransferase. J. Biol. Chem. 283, 6050–6057 (2008).

    Article  CAS  PubMed  Google Scholar 

  85. Taylor, R. P., Geisler, T. S., Chambers, J. H. & McClain, D. A. Up-regulation of O-GlcNAc transferase with glucose deprivation in HepG2 cells is mediated by decreased hexosamine pathway flux. J. Biol. Chem. 284, 3425–3432 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Song, M. et al. o-GlcNAc transferase is activated by CaMKIV-dependent phosphorylation under potassium chloride-induced depolarization in NG-108-15 cells. Cell. Signal. 20, 94–104 (2008).

    Article  CAS  PubMed  Google Scholar 

  87. Kreppel, L. K. & Hart, G. W. Regulation of a cytosolic and nuclear O-GlcNAc transferase. Role of the tetratricopeptide repeats. J. Biol. Chem. 274, 32015–32022 (1999). Demonstrates that the concentration of UDP-GlcNAc modulates the activity of OGT towards various peptide substrates.

    Article  CAS  PubMed  Google Scholar 

  88. Liu, K., Paterson, A. J., Chin, E. & Kudlow, J. E. Glucose stimulates protein modification by O-linked GlcNAc in pancreatic β cells: linkage of O-linked GlcNAc to β cell death. Proc. Natl Acad. Sci. USA 97, 2820–2825 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Isono, T. O-GlcNAc-specific antibody CTD110.6 cross-reacts with N-GlcNAc2-modified proteins induced under glucose deprivation. PLoS ONE 6, e18959 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Perez-Cervera, Y. et al. Insulin signaling controls the expression of O-GlcNAc transferase and its interaction with lipid microdomains. FASEB J. 27, 3478–3486 (2013).

    Article  CAS  PubMed  Google Scholar 

  91. Whelan, S. A., Lane, M. D. & Hart, G. W. Regulation of the O-linked β-N-acetylglucosamine transferase by insulin signaling. J. Biol. Chem. 283, 21411–21417 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Ruan, H. B. et al. O-GlcNAc transferase enables AgRP neurons to suppress browning of white fat. Cell 159, 306–317 (2014). Demonstrates that fasting-induced O -GlcNAcylation of a voltage-dependent potassium channel promotes excitation of appetite-stimulating neurons.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Lehman, D. M. et al. A single nucleotide polymorphism in MGEA5 encoding O-GlcNAc-selective N-acetyl-β-D glucosaminidase is associated with type 2 diabetes in Mexican Americans. Diabetes 54, 1214–1221 (2005).

    Article  CAS  PubMed  Google Scholar 

  94. Forsythe, M. E. et al. Caenorhabditis elegans ortholog of a diabetes susceptibility locus: oga-1 (O-GlcNAcase) knockout impacts O-GlcNAc cycling, metabolism, and dauer. Proc. Natl Acad. Sci. USA 103, 11952–11957 (2006). Demonstrates that knockout of either ogt-1 or oga-1 in C. elegans produces a metabolic phenotype of altered carbohydrate and lipid storage.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Hanover, J. A. et al. A Caenorhabditis elegans model of insulin resistance: altered macronutrient storage and dauer formation in an OGT-1 knockout. Proc. Natl Acad. Sci. USA 102, 11266–11271 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Qian, K., Ruan, H. B. & Yang, X. Y. Transcriptional regulation of O-GlcNAc homeostasis. FASEB J. 28 (Suppl.), 607.8 (2014).

    Google Scholar 

  97. Zhang, Z., Tan, E. P., VandenHull, N. J., Peterson, K. R. & Slawson, C. O-GlcNAcase expression is sensitive to changes in O-GlcNAc homeostasis. Front. Endocrinol. (Lausanne) 5, 206 (2014).

    Google Scholar 

  98. Khidekel, N. et al. Probing the dynamics of O-GlcNAc glycosylation in the brain using quantitative proteomics. Nat. Chem. Biol. 3, 339–348 (2007).

    Article  CAS  PubMed  Google Scholar 

  99. Torres, C. R. & Hart, G. W. Topography and polypeptide distribution of terminal N-acetylglucosamine residues on the surfaces of intact lymphocytes. Evidence for O-linked GlcNAc. J. Biol. Chem. 259, 3308–3317 (1984). Generally considered the first report to describe O -GlcNAcylation of intracellular proteins.

    CAS  PubMed  Google Scholar 

  100. Sinclair, D. A. et al. Drosophila O-GlcNAc transferase (OGT) is encoded by the Polycomb group (PcG) gene, super sex combs (sxc). Proc. Natl Acad. Sci. USA 106, 13427–13432 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Liu, T. W. et al. Genome-wide chemical mapping of O-GlcNAcylated proteins in Drosophila melanogaster. Nat. Chem. Biol. 13, 161–167 (2017).

    Article  PubMed  CAS  Google Scholar 

  102. Thornton, T. M., Swain, S. M. & Olszewski, N. E. Gibberellin signal transduction presents...the SPY who O-GlcNAc'd me. Trends Plant Sci. 4, 424–428 (1999).

    Article  CAS  PubMed  Google Scholar 

  103. Hartweck, L. M., Scott, C. L. & Olszewski, N. E. Two O-linked N-acetylglucosamine transferase genes of Arabidopsis thaliana L. Heynh. have overlapping functions necessary for gamete and seed development. Genetics 161, 1279–1291 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  104. Xu, S. L. et al. Proteomic analysis reveals O-GlcNAc modification on proteins with key regulatory functions in Arabidopsis. Proc. Natl Acad. Sci. USA 114, E1536–E1543 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Guo, B. et al. O-GlcNAc-modification of SNAP-29 regulates autophagosome maturation. Nat. Cell Biol. 16, 1215–1226 (2014).

    Article  CAS  PubMed  Google Scholar 

  106. Park, S. et al. O-GlcNAc modification is essential for the regulation of autophagy in Drosophila melanogaster. Cell. Mol. Life Sci. 72, 3173–3183 (2015).

    Article  CAS  PubMed  Google Scholar 

  107. Kim, E. Y. et al. A role for O-GlcNAcylation in setting circadian clock speed. Genes Dev. 26, 490–502 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Kaasik, K. et al. Glucose sensor O-GlcNAcylation coordinates with phosphorylation to regulate circadian clock. Cell Metab. 17, 291–302 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Olszewski, N. E., West, C. M., Sassi, S. O. & Hartweck, L. M. O-GlcNAc protein modification in plants: evolution and function. Biochim. Biophys. Acta 1800, 49–56 (2010).

    Article  CAS  PubMed  Google Scholar 

  110. Akan, I., Love, D. C., Harwood, K. R., Bond, M. R. & Hanover, J. A. Drosophila O-GlcNAcase deletion globally perturbs chromatin O-GlcNAcylation. J. Biol. Chem. 291, 9906–9919 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Sekine, O., Love, D. C., Rubenstein, D. S. & Hanover, J. A. Blocking O-linked GlcNAc cycling in Drosophila insulin-producing cells perturbs glucose-insulin homeostasis. J. Biol. Chem. 285, 38684–38691 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Wang, P. et al. O-GlcNAc cycling mutants modulate proteotoxicity in Caenorhabditis elegans models of human neurodegenerative diseases. Proc. Natl Acad. Sci. USA 109, 17669–17674 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Gambetta, M. C. & Muller, J. O-GlcNAcylation prevents aggregation of the Polycomb group repressor polyhomeotic. Dev. Cell 31, 629–639 (2014).

    Article  CAS  PubMed  Google Scholar 

  114. Love, D. C. et al. Dynamic O-GlcNAc cycling at promoters of Caenorhabditis elegans genes regulating longevity, stress, and immunity. Proc. Natl Acad. Sci. USA 107, 7413–7418 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Radermacher, P. T. et al. O-GlcNAc reports ambient temperature and confers heat resistance on ectotherm development. Proc. Natl Acad. Sci. USA 111, 5592–5597 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Lothrop, A. P., Torres, M. P. & Fuchs, S. M. Deciphering post-translational modification codes. FEBS Lett. 587, 1247–1257 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Allison, D. F. et al. Modification of RelA by O-linked N-acetylglucosamine links glucose metabolism to NF-κB acetylation and transcription. Proc. Natl Acad. Sci. USA 109, 16888–16893 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Hayakawa, K. et al. Epigenetic switching by the metabolism-sensing factors in the generation of orexin neurons from mouse embryonic stem cells. J. Biol. Chem. 288, 17099–17110 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Erickson, J. R. et al. Diabetic hyperglycaemia activates CaMKII and arrhythmias by O-linked glycosylation. Nature 502, 372–376 (2013). Demonstrates that hyperglycaemia-induced O -GlcNAcylation of CaMKII modulates calcium signalling and promotes arrhythmogenesis in the heart.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Yokoe, S. et al. Inhibition of phospholamban phosphorylation by O-GlcNAcylation: implications for diabetic cardiomyopathy. Glycobiology 20, 1217–1226 (2010).

    Article  CAS  PubMed  Google Scholar 

  121. Zhu-Mauldin, X., Marsh, S. A., Zou, L., Marchase, R. B. & Chatham, J. C. Modification of STIM1 by O-linked N-acetylglucosamine (O-GlcNAc) attenuates store-operated calcium entry in neonatal cardiomyocytes. J. Biol. Chem. 287, 39094–39106 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Hu, Y. et al. Increased enzymatic O-GlcNAcylation of mitochondrial proteins impairs mitochondrial function in cardiac myocytes exposed to high glucose. J. Biol. Chem. 284, 547–555 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Gawlowski, T. et al. Modulation of dynamin-related protein 1 (DRP1) function by increased O-linked-β-N-acetylglucosamine modification (O-GlcNAc) in cardiac myocytes. J. Biol. Chem. 287, 30024–30034 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Jones, S. P. et al. Cardioprotection by N-acetylglucosamine linkage to cellular proteins. Circulation 117, 1172–1182 (2008).

    Article  CAS  PubMed  Google Scholar 

  125. Banerjee, P. S., Ma, J. & Hart, G. W. Diabetes-associated dysregulation of O-GlcNAcylation in rat cardiac mitochondria. Proc. Natl Acad. Sci. USA 112, 6050–6055 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Watson, L. J. et al. O-Linked β-N-acetylglucosamine transferase is indispensable in the failing heart. Proc. Natl Acad. Sci. USA 107, 17797–17802 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Berrabah, W. et al. Glucose sensing O-GlcNAcylation pathway regulates the nuclear bile acid receptor farnesoid X receptor (FXR). Hepatology 59, 2022–2033 (2014).

    Article  CAS  PubMed  Google Scholar 

  128. Guinez, C. et al. O-GlcNAcylation increases ChREBP protein content and transcriptional activity in the liver. Diabetes 60, 1399–1413 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Alejandro, E. U. et al. Disruption of O-linked N-acetylglucosamine signaling induces ER stress and β cell failure. Cell Rep. 13, 2527–2538 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. McClain, D. A. et al. Altered glycan-dependent signaling induces insulin resistance and hyperleptinemia. Proc. Natl Acad. Sci. USA 99, 10695–10699 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Akimoto, Y. et al. Elevation of the post-translational modification of proteins by O-linked N-acetylglucosamine leads to deterioration of the glucose-stimulated insulin secretion in the pancreas of diabetic Goto–Kakizaki rats. Glycobiology 17, 127–140 (2007).

    Article  CAS  PubMed  Google Scholar 

  132. Soesanto, Y. et al. Pleiotropic and age-dependent effects of decreased protein modification by O-linked N-acetylglucosamine on pancreatic β-cell function and vascularization. J. Biol. Chem. 286, 26118–26126 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Swamy, M. et al. Glucose and glutamine fuel protein O-GlcNAcylation to control T cell self-renewal and malignancy. Nat. Immunol. 17, 712–720 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Zhang, D. et al. Modification of TAK1 by O-linked N-acetylglucosamine facilitates TAK1 activation and promotes M1 macrophage polarization. Cell. Signal. 28, 1742–1752 (2016).

    Article  CAS  PubMed  Google Scholar 

  135. Kneass, Z. T. & Marchase, R. B. Protein O-GlcNAc modulates motility-associated signaling intermediates in neutrophils. J. Biol. Chem. 280, 14579–14585 (2005).

    Article  CAS  PubMed  Google Scholar 

  136. Li, X. et al. O-Linked N-acetylglucosamine modification on CCAAT enhancer-binding protein β: role during adipocyte differentiation. J. Biol. Chem. 284, 19248–19254 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Ji, S., Park, S. Y., Roth, J., Kim, H. S. & Cho, J. W. O-GlcNAc modification of PPARγ reduces its transcriptional activity. Biochem. Biophys. Res. Commun. 417, 1158–1163 (2012).

    Article  CAS  PubMed  Google Scholar 

  138. Yang, Y. R. et al. Obesity resistance and increased energy expenditure by white adipose tissue browning in Oga+/− mice. Diabetologia 58, 2867–2876 (2015).

    Article  CAS  PubMed  Google Scholar 

  139. Hu, P., Berkowitz, P., Madden, V. J. & Rubenstein, D. S. Stabilization of plakoglobin and enhanced keratinocyte cell-cell adhesion by intracellular O-glycosylation. J. Biol. Chem. 281, 12786–12791 (2006).

    Article  CAS  PubMed  Google Scholar 

  140. Sohn, K. C. et al. Regulation of keratinocyte differentiation by O-GlcNAcylation. J. Dermatol. Sci. 75, 10–15 (2014).

    Article  CAS  PubMed  Google Scholar 

  141. Runager, K., Bektas, M., Berkowitz, P. & Rubenstein, D. S. Targeting O-glycosyltransferase (OGT) to promote healing of diabetic skin wounds. J. Biol. Chem. 289, 5462–5466 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Nagel, A. K. & Ball, L. E. O-GlcNAc modification of the runt-related transcription factor 2 (Runx2) links osteogenesis and nutrient metabolism in bone marrow mesenchymal stem cells. Mol. Cell. Proteomics 13, 3381–3395 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Koyama, T. & Kamemura, K. Global increase in O-linked N-acetylglucosamine modification promotes osteoblast differentiation. Exp. Cell Res. 338, 194–202 (2015).

    Article  CAS  PubMed  Google Scholar 

  144. Andres-Bergos, J. et al. The increase in O-linked N-acetylglucosamine protein modification stimulates chondrogenic differentiation both in vitro and in vivo. J. Biol. Chem. 287, 33615–33628 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Arias, E. B., Kim, J. & Cartee, G. D. Prolonged incubation in PUGNAc results in increased protein O-linked glycosylation and insulin resistance in rat skeletal muscle. Diabetes 53, 921–930 (2004).

    Article  CAS  PubMed  Google Scholar 

  146. Wang, X. et al. O-GlcNAcase deficiency suppresses skeletal myogenesis and insulin sensitivity in mice through the modulation of mitochondrial homeostasis. Diabetologia 59, 1287–1296 (2016).

    Article  CAS  PubMed  Google Scholar 

  147. Ogawa, M. et al. Terminal differentiation program of skeletal myogenesis is negatively regulated by O-GlcNAc glycosylation. Biochim. Biophys. Acta 1820, 24–32 (2012).

    Article  CAS  PubMed  Google Scholar 

  148. Ogawa, M., Sakakibara, Y. & Kamemura, K. Requirement of decreased O-GlcNAc glycosylation of Mef2D for its recruitment to the myogenin promoter. Biochem. Biophys. Res. Commun. 433, 558–562 (2013).

    Article  CAS  PubMed  Google Scholar 

  149. Rexach, J. E. et al. Dynamic O-GlcNAc modification regulates CREB-mediated gene expression and memory formation. Nat. Chem. Biol. 8, 253–261 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Su, C. & Schwarz, T. L. O-GlcNAc transferase is essential for sensory neuron survival and maintenance. J. Neurosci. 37, 2125–2136 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Pekkurnaz, G., Trinidad, J. C., Wang, X., Kong, D. & Schwarz, T. L. Glucose regulates mitochondrial motility via Milton modification by O-GlcNAc transferase. Cell 158, 54–68 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Wang, A. C., Jensen, E. H., Rexach, J. E., Vinters, H. V. & Hsieh-Wilson, L. C. Loss of O-GlcNAc glycosylation in forebrain excitatory neurons induces neurodegeneration. Proc. Natl Acad. Sci. USA 113, 15120–15125 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Lagerlof, O., Hart, G. W. & Huganir, R. L. O-GlcNAc transferase regulates excitatory synapse maturity. Proc. Natl Acad. Sci. USA 114, 1684–1689 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Taylor, E. W. et al. O-GlcNAcylation of AMPA receptor GluA2 is associated with a novel form of long-term depression at hippocampal synapses. J. Neurosci. 34, 10–21 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Lagerlof, O. et al. The nutrient sensor OGT in PVN neurons regulates feeding. Science 351, 1293–1296 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  156. Kim, S. et al. Schwann cell O-GlcNAc glycosylation is required for myelin maintenance and axon integrity. J. Neurosci. 36, 9633–9646 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Park, M. J. et al. High glucose-induced O-GlcNAcylated carbohydrate response element-binding protein (ChREBP) mediates mesangial cell lipogenesis and fibrosis: the possible role in the development of diabetic nephropathy. J. Biol. Chem. 289, 13519–13530 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Zeng, Q. et al. O-Linked GlcNAcylation elevated by HPV E6 mediates viral oncogenesis. Proc. Natl Acad. Sci. USA 113, 9333–9338 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Caldwell, S. A. et al. Nutrient sensor O-GlcNAc transferase regulates breast cancer tumorigenesis through targeting of the oncogenic transcription factor FoxM1. Oncogene 29, 2831–2842 (2010).

    Article  CAS  PubMed  Google Scholar 

  160. Rao, X. et al. O-GlcNAcylation of G6PD promotes the pentose phosphate pathway and tumor growth. Nat. Commun. 6, 8468 (2015).

    Article  CAS  PubMed  Google Scholar 

  161. Ferrer, C. M. et al. O-GlcNAcylation regulates cancer metabolism and survival stress signaling via regulation of the HIF-1 pathway. Mol. Cell 54, 820–831 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Jang, H. et al. O-GlcNAc regulates pluripotency and reprogramming by directly acting on core components of the pluripotency network. Cell Stem Cell 11, 62–74 (2012).

    Article  CAS  PubMed  Google Scholar 

  163. Myers, S. A. et al. SOX2 O-GlcNAcylation alters its protein-protein interactions and genomic occupancy to modulate gene expression in pluripotent cells. eLife 5, e10647 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

Download references

Acknowledgements

The authors thank all members of the Yang laboratory for stimulating discussions. This work was supported by grants from the US National Institutes of Health (R01DK089098, R01DK102648, P01DK057751), the American Cancer Society (RSG-14-244-01-TBE), the State of Connecticut (DPH2014-0139) and the Ellison Medical Foundation to X.Y.

Author information

Authors and Affiliations

  1. Department of Comparative Medicine, Department of Cellular and Molecular Physiology, Program in Integrative Cell Signaling and Neurobiology of Metabolism, Yale University School of Medicine, New Haven, 06510, Connecticut, USA

    Xiaoyong Yang & Kevin Qian

Authors
  1. Xiaoyong Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kevin Qian
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Xiaoyong Yang.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

PowerPoint slides

Glossary

Tetratricopeptide repeats

(TPRs). Thirty-four amino acid structural motifs that are found in tandem arrays in many proteins; they mediate protein–protein interactions and the assembly of protein complexes.

Molecular dynamics simulations

A computational method that simulates the physical movements of atoms and molecules; it can be used to model the internal motions and conformational changes of biological macromolecules to understand the physical basis of their structures and functions.

Orexin

A hypothalamic neuropeptide that regulates appetite, arousal and wakefulness; it is also known as hypocretin.

PPARγ co-activator 1α

(PGC1α). A transcriptional co-activator and master regulator of gluconeogenesis and mitochondrial biogenesis.

Gluconeogenesis

A metabolic pathway that produces glucose from various carbon sources that include glycerol, lactate and some amino acids; it occurs primarily in the liver and kidney in mammals.

Pyruvate kinase isoform M2

(PKM2). An isozyme of pyruvate kinase, the enzyme that catalyses the final step of glycolysis; it has been implicated in the reprogramming of metabolic pathways in cancer.

Aerobic glycolysis

The preferential utilization of glycolysis and lactic acid fermentation for ATP production despite the availability of oxygen for oxidative phosphorylation; it is a hallmark of metabolic reprogramming in cancer.

Lectin

A protein that recognizes and binds to specific carbohydrates; these carbohydrates can be monosaccharides or oligosaccharides, and they can be soluble or attached to glycolipids and glycoproteins.

Molecular docking simulations

A computational method that simulates the process of a ligand binding to an enzyme or receptor; it can be used to predict the preferred orientation of a ligand in the active site of an enzyme.

Transactivation

The increased expression of a gene that is induced by the expression of a transactivator protein (for example, a transcription factor); transcription factors possess transactivation domains that contain binding sites for transcriptional co-regulators.

Transrepression

The repression of the activity of one protein (for example, a transcription factor) through its interaction with a second protein.

Pre-initiation complex

A large protein assembly that performs various functions that are required for transcription initiation (for example, the recruitment of RNA polymerase II to transcription start sites and the unwinding of DNA to allow for RNA polymerase II binding).

Lipid rafts

Cholesterol- and sphingolipid-enriched microdomains in the plasma membrane, which serve as organizing centres for signal transduction.

Ketogenesis

The production of ketone bodies (acetoacetate, acetone and β-hydroxybutyrate) from the catabolism of fatty acids and some amino acids; ketone bodies become a major energy source for various organs during fasting and for the brain during long-term starvation.

Browning of white adipose tissue

The increased white adipose tissue expression of uncoupling protein 1 (UCP1), which is typically found in the mitochondria of brown adipose tissue; UCP1 uncouples the electron transport chain from ATP production to generate heat.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Yang, X., Qian, K. Protein O-GlcNAcylation: emerging mechanisms and functions. Nat Rev Mol Cell Biol 18, 452–465 (2017). https://doi.org/10.1038/nrm.2017.22

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrm.2017.22

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing