Fbxo7 promotes Cdk6 activity to inhibit PFKP and glycolysis in T cells.
J Cell Biol
Rockefeller University Press
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Harris, R., Yang, M., Schmidt, C., Royet, C., Singh, S., Natarajan, A., Morris, M., et al. (2022). Fbxo7 promotes Cdk6 activity to inhibit PFKP and glycolysis in T cells.. J Cell Biol https://doi.org/10.1083/jcb.202203095
Fbxo7 is associated with cancer and Parkinson's disease. Although Fbxo7 recruits substrates for SCF-type ubiquitin ligases, it also promotes Cdk6 activation in a ligase-independent fashion. We discovered PFKP, the gatekeeper of glycolysis, in a screen for Fbxo7 substrates. PFKP is an essential Cdk6 substrate in some T-ALL cells. We investigated the molecular relationship between Fbxo7, Cdk6, and PFKP, and the effect of Fbxo7 on T cell metabolism, viability, and activation. Fbxo7 promotes Cdk6-independent ubiquitination and Cdk6-dependent phosphorylation of PFKP. Importantly, Fbxo7-deficient cells have reduced Cdk6 activity, and hematopoietic and lymphocytic cells show high expression and significant dependency on Fbxo7. CD4+ T cells with reduced Fbxo7 show increased glycolysis, despite lower cell viability and activation levels. Metabolomic studies of activated CD4+ T cells confirm increased glycolytic flux in Fbxo7-deficient cells, alongside altered nucleotide biosynthesis and arginine metabolism. We show Fbxo7 expression is glucose-responsive at the mRNA and protein level and propose Fbxo7 inhibits PFKP and glycolysis via its activation of Cdk6.
Cancer Research UK
Cancer Research UK (C9685/A25166)
External DOI: https://doi.org/10.1083/jcb.202203095
This record's URL: https://www.repository.cam.ac.uk/handle/1810/345018
Attribution 4.0 International (CC BY)
Licence URL: http://creativecommons.org/licenses/by/4.0/