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The metabolic enzyme GYS1 condenses with NONO/p54nrb in the nucleus and spatiotemporally regulates glycogenesis and myogenic differentiation

Cell Death & Differentiation (2025)Cite this article

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Abstract

Accumulating evidence indicates that metabolic enzymes can directly couple metabolic signals to transcriptional adaptation and cell differentiation. Glycogen synthase 1 (GYS1), the key metabolic enzyme for glycogenesis, is a nucleocytoplasmic shuttling protein compartmentalized in the cytosol and nucleus. However, the spatiotemporal regulation and biological function of nuclear GYS1 (nGYS1) microcompartments remain unclear. Here, we show that GYS1 dynamically reorganizes into nuclear condensates under conditions of glycogen depletion or transcription inhibition. nGYS1 complexes with the transcription factor NONO/p54nrb and undergoes liquid–liquid phase separation to form biomolecular condensates, leading to its nuclear retention and inhibition of glycogen biosynthesis. Compared to their wild-type littermates, Nono-deficient mice exhibit exercise intolerance, higher muscle glycogen content, and smaller myofibers. Additionally, Gys1 or Nono deficiency prevents C2C12 differentiation and cardiotoxin-induced muscle regeneration in mice. Mechanistically, nGYS1 and NONO co-condense with the myogenic transcription factor MyoD and preinitiation complex (PIC) proteins to form transcriptional condensates, driving myogenic gene expression during myoblast differentiation. These results reveal the spatiotemporal regulation and subcellular function of nuclear GYS1 condensates in glycogenesis and myogenesis, providing mechanistic insights into glycogenoses and muscular dystrophy.

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Fig. 1: Reassembly of subcellular GYS1 protein bodies under energy or transcription stress conditions.
Fig. 2: nGYS1 interacts with and condenses NONO in cells.
Fig. 3: NONO condenses GYS1 in the nucleus to inhibit glycogenesis and support strenuous exercise in mice.
Fig. 4: GYS1 protein phase separates and co-condensates with NONO in vitro.
Fig. 5: The nGYS1 condensates are more dynamic than the glycosome GYS1.
Fig. 6: Nono deficiency leads to myogenic defects in mouse skeletal muscle.
Fig. 7: GYS1-NONO co-condenses with MyoD and Pol II to regulate myogenic gene transcription.
Fig. 8: A diagram depicting the spatiotemporal regulation and subcellular function of GYS1.

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Data availability

All data necessary to evaluate the conclusions of this study are presented in the paper and/or the supplementary information. The mass spectrometry proteomics data have been deposited in the ProteomeXchange Consortium via the PRIDE partner repository, with dataset identifiers PXD051836 and PXD058561.

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Acknowledgements

We thank the Core Facilities at the State Key Laboratory of Oncology in South China and the Medical Science Public Platform of Shenzhen Campus, Sun Yat-sen University, for their assistance with imaging experiments. The mScarlet-labeled MS2-tagged Neat1_2 knock-in cell line was provided by Professor Zhou Songyang from Sun Yat-sen University. The GYS2 and SC35 cDNAs were provided by Professor Ronggui Hu at the Shanghai Institute of Biochemistry and Cell Biology, while the AAV vectors were provided by Professor Qiurong Ding from the Shanghai Institute of Nutrition and Health.

Funding

This project is supported by the National Natural Science Foundation of China (No. 31871439 to XX, No. 32425019 to ZG), Ministry of Science and Technology of China (National Key R&D Program of China 2022YFA0806000) to ZG, the Shenzhen Science and Technology Program (JCYJ20240813151133043 and JCYJ20220530145613030 to XX), the Guangdong Basic and Applied Basic Research Foundation (2023A1515011923 to XX), and the Open Funds from the State Key Laboratory of Oncology in South China (HN2022-02 to XX and LF).

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  1. These authors contributed equally: Shujun Peng, Canrong Li, Yifan Wang, Yuguo Yi.

Authors and Affiliations

  1. School of Medicine, Shenzhen Campus of Sun Yat-sen University, Sun Yat-sen University, Shenzhen, PR China

    Shujun Peng, Canrong Li, Yifan Wang, Yuguo Yi, Xinyu Chen, Fan Yang, Fengzhi Chen, Yingyi Ouyang, Haolun Xu, Baicheng Chen, Haowen Shi, Yu Zhao & Xiaoduo Xie

  2. State Key Laboratory of Pharmaceutical Biotechnology and MOE Key Laboratory of Model Animal for Disease Study, Medical School of Nanjing University, Nanjing University, Nanjing, PR China

    Yujing Yin & Zhenji Gan

  3. CAS Key Laboratory of Systems Biology, Center for Excellence in Molecular Cell Sciences, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai, PR China

    Qingrun Li

  4. Department of Experimental Research, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, PR China

    Lin Feng

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  1. Shujun Peng
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Contributions

X Xie conceived the idea; S Peng, C Li, Y Wang, Y Yi, X Chen, Y Yin, Z Gan, and X Xie designed and performed the experiments, with contributions from F Yang, F Chen, Y Ouyang, H Xu, B Chen, H Shi, Y Zhao, and L Feng; Q Li performed TurboID MS analysis. S Peng, C Li, Y Wang, Y Yi, Z Gan, and X Xie analyzed the data and wrote the manuscript with input from all other authors. L Feng, Z Gan, and X Xie supervised the project.

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Correspondence to Lin Feng, Zhenji Gan or Xiaoduo Xie.

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Peng, S., Li, C., Wang, Y. et al. The metabolic enzyme GYS1 condenses with NONO/p54nrb in the nucleus and spatiotemporally regulates glycogenesis and myogenic differentiation. Cell Death Differ (2025). https://doi.org/10.1038/s41418-025-01509-4

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