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.
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Acknowledgements
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.
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W.Y. conceived and designed the study. W.Z., X.W., Y.Zhang, H.Y., and H.Z. performed the experiments. G.L. designed the molecular dynamics strategy. G.L., H.C., and Y.L. performed the simulations and data analysis. T.L. and Q.L. provided reagents and pathological assistance. H.G. assisted in reviewing the paper. Y.Zhao provided constructive suggestions. W.Y. and G.L. wrote the manuscript with comments from all authors.
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Zhu, W., Chu, H., Zhang, Y. et al. Fructose-1,6-bisphosphatase 1 dephosphorylates IκBα and suppresses colorectal tumorigenesis. Cell Res 33, 245–257 (2023). https://doi.org/10.1038/s41422-022-00773-0
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DOI: https://doi.org/10.1038/s41422-022-00773-0
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