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Crosstalk between O-GlcNAcylation and phosphorylation in metabolism: regulation and mechanism

Cell Death & Differentiation volume 32, pages 1181–1199 (2025)Cite this article

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Abstract

Cells produce metabolic intermediates through catalytic reactions, mainly via post-translational modifications. The modification of proteins by O-linked N-acetylglucosamine, known as O-GlcNAcylation, is one of the most common post-translational modifications. As O-GlcNAcylation and phosphorylation can occur at serine or threonine residues, it is crucial that the interplay between these two modifications is vital to bioenergetic and biosynthetic demand. Although emerging recognition linking O-GlcNAc modification and phosphorylation to protein functions has been obtained, the issue of how altered O-GlcNAcylation or phosphorylation regulates each other in the metabolic system remains uncertain. The combination of cell biological and proteomic approaches over the recent few years has not only highlighted the interactions between O-GlcNAcylation and phosphorylation in protein function but also prompted us to elucidate the underlying mechanisms behind this crosstalk controlling metabolic homeostasis. The purpose of this review is to summarize recent advances in the O-GlcNAcylation/phosphorylation regulation of the metabolic process. An extensive exploration of this interplay has significant implications for metabolic control systems, including glucose, lipid, and nucleotide metabolism, where dysregulation in O-GlcNAcylation and phosphorylation of metabolic syndrome is essential.

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Fig. 1: The HBP pathway and O-GlcNAcylation produced by HBP.
Fig. 2: In metabolism, the O-GlcNAcylation of protein can inhibit the phosphorylation.
Fig. 3: In metabolism, protein phosphorylation can inhibit O-GlcNAcylation.
Fig. 4: Mechanism of the crosstalk between O-GlcNAcylation and phosphorylation.
Fig. 5: Crosstalk between O-GlcNAcylation and phosphorylation in metabolism.

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Acknowledgements

We would like to thank the members of the Qian and Xu laboratories for helpful discussions. Thanks to Jiajia Song for her advice and encouragement.

Funding

This work has been supported by National Natural Science Foundation of China (grant No. 32000903), and the Scientific Research Foundation of Jiangsu University for Senior Professional Talents (20JDG48).

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  1. These authors contributed equally: Qijie Zhao, Shisheng Zhou, Wenhui Lou.

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  1. Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, Department of Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, China

    Qijie Zhao, Shisheng Zhou, Wenhui Lou, Hui Qian & Zhiwei Xu

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  1. Qijie Zhao
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QJZ and ZWX conceived and wrote the first draft of both text and figures. SSZ, WHL, and HQ conceptualized, wrote, revised, and edited the manuscript.

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Zhao, Q., Zhou, S., Lou, W. et al. Crosstalk between O-GlcNAcylation and phosphorylation in metabolism: regulation and mechanism. Cell Death Differ 32, 1181–1199 (2025). https://doi.org/10.1038/s41418-025-01473-z

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