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Fructose-1,6-bisphosphatase 1 dephosphorylates I kappa B alpha and suppresses colorectal tumorigenesis

文献类型：期刊论文

作者Zhu, Wencheng2; Chu, Huiying3; Zhang, Yajuan2; Luo, Tianhang4; Yu, Hua5; Zhu, Hongwen6; Liu, Ye3; Gao, Hong2; Zhao, Yun2,7; Li, Quanlin1,8
刊名CELL RESEARCH
出版日期2023-01-16
页码13
ISSN号1001-0602
DOI10.1038/s41422-022-00773-0
通讯作者Li, Quanlin(li.quanlin@zs-hospital.sh.cn) ; Wang, Xiongjun(wangxiongjun@gzhu.edu.cn) ; Li, Guohui(ghli@dicp.ac.cn) ; Yang, Weiwei(wyang@sibcb.ac.cn)
英文摘要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 I kappa B alpha as the substrate of FBP1-mediated dephosphorylation by performing phosphoproteomic analysis. Mechanistically, FBP1 directly interacts with and dephosphorylates the serine (S) 32/36 of I kappa B alpha upon TNF alpha stimulation, thereby inhibiting NF-kappa B activation. MD simulations indicate that the catalytic mechanism of FBP1-mediated I kappa B alpha dephosphorylation is similar to F-1,6-BP dephosphorylation, except for higher energetic barriers for I kappa B alpha dephosphorylation. Functionally, FBP1-dependent NF-kappa B 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 I kappa B alpha dephosphorylation in colorectal tumorigenesis.
WOS关键词MOLECULAR-DYNAMICS ; INFLAMMATION ; IMMUNITY ; ACTIVATION ; SOFTWARE ; CANCER ; CELLS
资助项目National Natural Science Foundation of China[92253305] ; National Natural Science Foundation of China[92053203] ; National Natural Science Foundation of China[32025013] ; National Natural Science Foundation of China[SHSMU-ZLCX20212302] ; National Natural Science Foundation of China[XDB 37000000] ; National Key R&D Program of China[2022YFA0806201] ; National Key R&D Program of China[2019YFA0802000] ; CAS Project for Young Scientists in Basic Research[YSBR-014] ; Program of Shanghai Academic/Technology Research Leader[20XD1424400] ; Innovative Research Team of High-level Local Universities in Shanghai[21933010] ; Strategic Priority Research Program of Chinese Academy of Sciences[21907094] ; Youth Innovation Promotion Association of the Chinese Academy of Sciences[2022265] ; Shanghai Science and Technology Development Funds[22QA1409900] ; Sanofi Scholarship Program
WOS研究方向Cell Biology
语种英语
出版者SPRINGERNATURE
WOS记录号WOS:000916911600003
源URL[http://119.78.100.183/handle/2S10ELR8/303684]  
专题中国科学院上海药物研究所
通讯作者Li, Quanlin; Wang, Xiongjun; Li, Guohui; Yang, Weiwei
作者单位1.Fudan Univ, Endoscopy Ctr, Shanghai, Peoples R China
2.Univ Chinese Acad Sci, Chinese Acad Sci, Shanghai Inst Biochem & Cell Biol, Ctr Excellence Mol Cell Sci,State Key Lab Cell Bio, Shanghai, Peoples R China
3.Chinese Acad Sci, Dalian Inst Chem Phys, Lab Mol Modeling, State Key Lab Mol React Dynam, Dalian, Liaoning, Peoples R China
4.Second Mil Med Univ, Changhai Hosp, Dept Gen Surg, Shanghai, Peoples R China
5.Guangzhou Univ, Precise Genome Engn Ctr, Sch Life Sci, Guangzhou, Guangdong, Peoples R China
6.Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai, Peoples R China
7.Univ Chinese Acad Sci, Hangzhou Inst Adv Study, Sch Life Sci, Key Lab Syst Hlth Sci Zhejiang Prov, Hangzhou, Zhejiang, Peoples R China
8.Fudan Univ, Zhongshan Hosp, Endoscopy Res Inst, Shanghai, Peoples R China
推荐引用方式
GB/T 7714		 Zhu, Wencheng,Chu, Huiying,Zhang, Yajuan,et al. Fructose-1,6-bisphosphatase 1 dephosphorylates I kappa B alpha and suppresses colorectal tumorigenesis[J]. CELL RESEARCH,2023:13.
APA Zhu, Wencheng.,Chu, Huiying.,Zhang, Yajuan.,Luo, Tianhang.,Yu, Hua.,...&Yang, Weiwei.(2023).Fructose-1,6-bisphosphatase 1 dephosphorylates I kappa B alpha and suppresses colorectal tumorigenesis.CELL RESEARCH,13.
MLA Zhu, Wencheng,et al."Fructose-1,6-bisphosphatase 1 dephosphorylates I kappa B alpha and suppresses colorectal tumorigenesis".CELL RESEARCH (2023):13.

入库方式： OAI收割

来源：上海药物研究所

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