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.