中国科学院分子细胞科学卓越创新中心杨巍维等研究人员合作发现，果糖-1,6-双磷酸酶1能够去磷酸化IκBα并抑制结直肠肿瘤的发生。相关论文于2023年1月16日在线发表在《细胞研究》杂志上。

通过对代谢性磷酸酶进行高通量筛选，并进行分子动力学（MD）模拟，研究人员将催化1,6-二磷酸果糖（F-1,6-BP）水解为6-磷酸果糖（F-6-P）的糖异生酶鉴定为一种蛋白磷酸酶。此外，通过进行磷蛋白组分析，研究人员确定了IκBα是FBP1介导的去磷酸化底物。从机制上讲，FBP1在TNFα刺激下直接与IκBα的丝氨酸（S）32/36相互作用并去磷酸化，从而抑制了NF-κB的激活。MD模拟表明，FBP1介导的IκBα去磷酸化的催化机制与F-1,6-BP去磷酸化相似，只是IκBα去磷酸化的能量障碍更高。在功能上，FBP1依赖的NF-κB失活通过使肿瘤细胞对炎症压力敏感和阻止骨髓源性抑制细胞的动员来抑制结直肠肿瘤的发生。这项发现揭示了FBP1作为蛋白磷酸酶的一个新作用，并确定了FBP1介导的IκBα去磷酸化在结直肠肿瘤发生中的关键作用。

附：英文原文

Title: Fructose-1,6-bisphosphatase 1 dephosphorylates IκBα and suppresses colorectal tumorigenesis

Author: Zhu, Wencheng, Chu, Huiying, Zhang, Yajuan, Luo, Tianhang, Yu, Hua, Zhu, Hongwen, Liu, Ye, Gao, Hong, Zhao, Yun, Li, Quanlin, Wang, Xiongjun, Li, Guohui, Yang, Weiwei

Issue&Volume: 2023-01-16

Abstract: Emerging evidence demonstrates that some metabolic enzymes that phosphorylate soluble metabolites can also phosphorylate a variety of protein substrates as protein kinases to regulate cell cycle, apoptosis and many other fundamental cellular processes. However, whether a metabolic enzyme dephosphorylates protein as a protein phosphatase remains unknown. Here we reveal the gluconeogenic enzyme fructose 1,6-biphosphatase 1 (FBP1) that catalyzes the hydrolysis of fructose 1,6-bisphosphate (F-1,6-BP) to fructose 6-phosphate (F-6-P) as a protein phosphatase by performing a high-throughput screening of metabolic phosphatases with molecular docking followed by molecular dynamics (MD) simulations. Moreover, we identify IκBα as the substrate of FBP1-mediated dephosphorylation by performing phosphoproteomic analysis. Mechanistically, FBP1 directly interacts with and dephosphorylates the serine (S) 32/36 of IκBα upon TNFα stimulation, thereby inhibiting NF-κB activation. MD simulations indicate that the catalytic mechanism of FBP1-mediated IκBα dephosphorylation is similar to F-1,6-BP dephosphorylation, except for higher energetic barriers for IκBα dephosphorylation. Functionally, FBP1-dependent NF-κB inactivation suppresses colorectal tumorigenesis by sensitizing tumor cells to inflammatory stresses and preventing the mobilization of myeloid-derived suppressor cells. Our finding reveals a previously unrecognized role of FBP1 as a protein phosphatase and establishes the critical role of FBP1-mediated IκBα dephosphorylation in colorectal tumorigenesis.

DOI: 10.1038/s41422-022-00773-0

Source: https://www.nature.com/articles/s41422-022-00773-0