Lin Pianpian, Qi Yijun, Chu Huiying, Wu Hongyu, Zhang Yajuan, Huang Xiaolan, Li Chen, Xu Xiaoyan, Gao Hong, Zeng Rong, Li Guohui, Yang Weiwei
Key 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.
Key Laboratory of Systems Health Science of Zhejiang Province, School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, China.
Nat Commun. 2025 Jul 22;16(1):6736. doi: 10.1038/s41467-025-62111-3.
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.
新出现的证据表明，代谢信号——包括营养物质可用性、生物合成中间体和能量平衡——与细胞周期进程相关联。然而，细胞周期机制如何感知这些信号仍不清楚。柠檬酸是三羧酸循环中的关键中间体，在有丝分裂（M期）达到峰值，并被糖酵解酶ATP依赖性6-磷酸果糖激酶1肌肉亚型（PFKM）检测到，从而加速有丝分裂进程。从机制上讲，柠檬酸与PFKM结合，将其四聚体结构破坏成二聚体。二聚体PFKM与核小体相互作用，并使组蛋白H3的丝氨酸10（H3S10）磷酸化，作为一种蛋白激酶促进有丝分裂和细胞增殖。结构模拟显示，当H3S10与其催化位点对齐时，PFKM能最佳地结合核小体。破坏柠檬酸-PFKM或PFKM-H3相互作用会减少H3S10磷酸化，延迟有丝分裂，并抑制肿瘤生长和T细胞增殖。我们的研究结果表明，PFKM作为一种柠檬酸传感器，将代谢信号与细胞周期调控联系起来。
