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PFKM phosphorylates histone H3 and promotes mitotic progression by sensing the levels of citrate

Author

Listed:
  • Pianpian Lin

    (Shanghai Institute of Biochemistry and Cell Biology)

  • Yijun Qi

    (University of Chinese Academy of Sciences)

  • Huiying Chu

    (Liaoning Normal University)

  • Hongyu Wu

    (Shanghai Institute of Biochemistry and Cell Biology)

  • Yajuan Zhang

    (Shanghai Institute of Biochemistry and Cell Biology)

  • Xiaolan Huang

    (University of Chinese Academy of Sciences)

  • Chen Li

    (Shanghai Jiao Tong University School of Medicine)

  • Xiaoyan Xu

    (Westlake University)

  • Hong Gao

    (Shanghai Institute of Biochemistry and Cell Biology)

  • Rong Zeng

    (Shanghai Institute of Biochemistry and Cell Biology
    ShanghaiTech University
    Chinese Academy of Sciences
    ShanghaiTech University)

  • Guohui Li

    (Liaoning Normal University)

  • Weiwei Yang

    (Shanghai Institute of Biochemistry and Cell Biology
    University of Chinese Academy of Sciences
    Shanghai Academy of Natural Sciences (SANS))

Abstract

Emerging evidence indicates that metabolic signals—including nutrient availability, biosynthetic intermediates, and energy balance—are linked to cell cycle progression. However, how these signals are sensed by the cell cycle machinery remains unclear. Citrate, a key intermediate in the TCA cycle, peaks during mitosis (M phase) and is detected by the glycolytic enzyme ATP-dependent 6-phosphofructokinase 1 muscle isoform (PFKM), accelerating mitotic progression. Mechanistically, citrate binds PFKM, disrupting its tetrameric structure into dimers. Dimeric PFKM interacts with nucleosomes and phosphorylates histone H3 at serine 10 (H3S10), functioning as a protein kinase to promote mitosis and cell proliferation. Structural simulations reveal that PFKM binds nucleosomes optimally when H3S10 aligns with its catalytic site. Disrupting citrate-PFKM or PFKM-H3 interactions reduces H3S10 phosphorylation, delays mitosis, and suppresses tumor growth and T-cell proliferation. Our findings demonstrate that PFKM acts as a citrate sensor, coupling metabolic signals to cell cycle regulation.

Suggested Citation

  • Pianpian Lin & Yijun Qi & Huiying Chu & Hongyu Wu & Yajuan Zhang & Xiaolan Huang & Chen Li & Xiaoyan Xu & Hong Gao & Rong Zeng & Guohui Li & Weiwei Yang, 2025. "PFKM phosphorylates histone H3 and promotes mitotic progression by sensing the levels of citrate," Nature Communications, Nature, vol. 16(1), pages 1-20, December.
  • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-62111-3
    DOI: 10.1038/s41467-025-62111-3
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