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

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

机构地区：[1]State Key Laboratory of Cell Biology,Shanghai Institute of Biochemistry and Cell Biology,Center for Excellence in Molecular Cell Science,Chinese Academy of Sciences,University of Chinese Academy of Sciences,Shanghai,China [2]Laboratory of Molecular Modeling,State Key Lab of Molecular Reaction Dynamics,Dalian Institute of Chemical Physics,Chinese Academy of Sciences,Dalian,Liaoning,China [3]Department of General Surgery,Changhai Hospital,The Second Military Medical University,Shanghai,China [4]Precise Genome Engineering Center,School of Life Sciences,Guangzhou University,Guangzhou,Guangdong,China [5]Shanghai Institute of Materia Medica,Chinese Academy of Sciences,Shanghai,China [6]Key Laboratory of Systems Health Science of Zhejiang Province,School of Life Sciences,Hangzhou Institute for Advanced Study,University of Chinese Academy of Sciences,Hangzhou,Zhejiang,China [7]Endoscopy Center and Endoscopy Research Institute,Zhongshan Hospital,Fudan University,Shanghai,China

出　　处：《Cell Research》2023年第3期245-257,共13页细胞研究（英文版）

基　　金：This work was supported by the National Natural Science Foundation of China(92253305,92053203 and 32025013)to W.Y.;the National Key R&D Program of China(2022YFA0806201 and 2019YFA0802000)to W.Y.;CAS Project for Young Scientists in Basic Research(YSBR-014)to W.Y.;Program of Shanghai Academic/Technology Research Leader(20XD1424400)to W.Y.;the Innovative Research Team of High-level Local Universities in Shanghai(SHSMU-ZLCX20212302)to W.Y.;the Strategic Priority Research Program of Chinese Academy of Sciences(XDB 37000000)to G.L.;the National Natural Science Foundation of China(21933010)to G.L.;the National Natural Science Foundation of China(21907094)to H.C.;the Youth Innovation Promotion Association of the Chinese Academy of Sciences(2022265)to Y.Zhang;Shanghai Science and Technology Development Funds(22QA1409900)to Y.Zhang.We gratefully acknowledge the support of the Sanofi Scholarship Program.We also thank all the core facilities of Shanghai Institute of Biochemistry and Cell Biology for technical support.

摘　　要：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 IκBαas the substrate of FBP1-mediated dephosphorylation by performing phosphoproteomic analysis.Mechanistically,FBP1 directly interacts with and dephosphorylates the serine(S)32/36 of IκBαupon TNFαstimulation,thereby inhibiting NF-κB activation.MD simulations indicate that the catalytic mechanism of FBP1-mediated IκBαdephosphorylation is similar to F-1,6-BP dephosphorylation,except for higher energetic barriers for IκBαdephosphorylation.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 IκBαdephosphorylation in colorectal tumorigenesis.

关 键 词：IΚBΑ COLORECTAL STIMULATION 

分 类 号：R735.37[医药卫生—肿瘤]