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O-GlcNAc occurs cotranslationally to stabilize nascent polypeptide chains

Nature Chemical Biology volume 11, pages 319–325 (2015)Cite this article

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Abstract

Nucleocytoplasmic glycosylation of proteins with O-linked N-acetylglucosamine residues (O-GlcNAc) is recognized as a conserved post-translational modification found in all metazoans. O-GlcNAc has been proposed to regulate diverse cellular processes. Impaired cellular O-GlcNAcylation has been found to lead to decreases in the levels of various proteins, which is one mechanism by which O-GlcNAc seems to exert its varied physiological effects. Here we show that O-GlcNAcylation also occurs cotranslationally. This process protects nascent polypeptide chains from premature degradation by decreasing cotranslational ubiquitylation. Given that hundreds of proteins are O-GlcNAcylated within cells, our findings suggest that cotranslational O-GlcNAcylation may be a phenomenon regulating proteostasis of an array of nucleocytoplasmic proteins. These findings set the stage to assess whether O-GlcNAcylation has a role in protein quality control in a manner that bears similarity with the role played by N-glycosylation within the secretory pathway.

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Figure 1: Sp1 is cotranslationally O-GlcNAcylated in a cell-free expression system.
Figure 2: Nascent Sp1 polypeptides are stabilized by cotranslational O-GlcNAcylation in a cell-free system.
Figure 3: Cotranslational O-GlcNAcylation of Sp1 stabilizes nascent polypeptides within cells.
Figure 4: Cotranslational O-GlcNAcylation of Sp1 stabilizes nascent polypeptides from premature proteasomal degradation within cells.
Figure 5: Proposed model for regulation of nascent polypeptide chain stability by cotranslational O-GlcNAcylation.

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Acknowledgements

Financial support through a Discovery Grant (grant number: RGPIN/298406-2010) the Natural Sciences and Engineering Research (NSERC) and the Canadian Institutes of Health Research (CIHR; grant number: MOP-123341) is gratefully acknowledged. Y.Z. thanks the CIHR for support through a postdoctoral fellowship. D.J.V. acknowledges the kind support of the Canada Research Chairs program for a Tier I Canada Research Chair in Chemical Glycobiology and NSERC for support as an E.W.R. Steacie Memorial Fellow. S.C. acknowledges the Government of Canada and the CIHR for postdoctoral fellowship support. R.E. acknowledges the Alzheimer Society of Canada and the Michael Smith Foundation for Health Research for postdoctoral fellowship support.

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Authors and Affiliations

  1. Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, British Columbia, Canada.,

    Yanping Zhu, Ta-Wei Liu & David J Vocadlo

  2. Department of Chemistry, Simon Fraser University, Burnaby, British Columbia, Canada..,

    Yanping Zhu, Ta-Wei Liu, Samy Cecioni, Razieh Eskandari, Wesley F Zandberg & David J Vocadlo

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Contributions

Y.Z. and D.J.V. designed research; Y.Z. and T.-W.L. performed experiments; R.E. synthesized UDP-GlcNAz; W.F.Z. synthesized UDP-5SGlcNAc; S.C. synthesized the biotin-diazo-phosphine probe; Y.Z. and D.J.V. wrote the paper; all authors provided input into the manuscript.

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Correspondence to David J Vocadlo.

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Competing interests

D.J.V. is a cofounder of Alectos Therapeutics, a company involved in the development of OGA modulators for the treatment of Alzheimer's disease. D.J.V. serves as CSO and chair of the Scientific Advisory Board of Alectos Therapeutics.

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Zhu, Y., Liu, TW., Cecioni, S. et al. O-GlcNAc occurs cotranslationally to stabilize nascent polypeptide chains. Nat Chem Biol 11, 319–325 (2015). https://doi.org/10.1038/nchembio.1774

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