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Updated: Sep 14, 2025

Identification of Cyclin-dependent Kinase 1 Specific Phosphorylation Sites by an In Vitro Kinase Assay
Published on: May 3, 2018
PFKM phosphorylates histone H3 and promotes mitotic progression by sensing the levels of citrate
Pianpian Lin1, Yijun Qi2, Huiying Chu3
1Key Laboratory of Multi-cell Systems, Shanghai Key Laboratory of Molecular Andrology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai Institute of Biochemistry and Cell Biology, Shanghai, China.
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.
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