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Volume 33, No 3, Mar 2023

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 33 Issue 3, March 2023: 245-257

ORIGINAL ARTICLES

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

Wencheng Zhu1,† , Huiying Chu2,† , Yajuan Zhang1,† , Tianhang Luo3,† , Hua Yu4,† , Hongwen Zhu5 , Ye Liu2 , Hong Gao1 , Yun Zhao1,6 , Quanlin Li7,* , Xiongjun Wang4,* , Guohui Li2,* , Weiwei Yang1,6,*

1State 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
2Laboratory of Molecular Modeling, State Key Lab of Molecular Reaction Dynamics, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, Liaoning, China
3Department of General Surgery, Changhai Hospital, The Second Military Medical University, Shanghai, China
4Precise Genome Engineering Center, School of Life Sciences, Guangzhou University, Guangzhou, Guangdong, China
5Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
6Key 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
7Endoscopy Center and Endoscopy Research Institute, Zhongshan Hospital, Fudan University, Shanghai, China
These authors contributed equally: Wencheng Zhu, Huiying Chu, Yajuan Zhang, Tianhang Luo, Hua Yu
Correspondence: Quanlin Li(li.quanlin@zs-hospital.sh.cn)Xiongjun Wang(wangxiongjun@gzhu.edu.cn)Guohui Li(ghli@dicp.ac.cn)Weiwei Yang(wyang@sibcb.ac.cn)

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.


https://doi.org/10.1038/s41422-022-00773-0

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