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Article Dans Une Revue Journal of Cell Biology Année : 2022

Fbxo7 promotes Cdk6 activity to inhibit PFKP and glycolysis in T cells

Rebecca Harris
Christina Schmidt
Sarbjit Singh
Christian Frezza
Heike Laman

Résumé

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.
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hal-03808039 , version 1 (10-10-2022)

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Rebecca Harris, Ming Yang, Christina Schmidt, Chloe Royet, Sarbjit Singh, et al.. Fbxo7 promotes Cdk6 activity to inhibit PFKP and glycolysis in T cells. Journal of Cell Biology, 2022, 221 (7), ⟨10.1083/jcb.202203095⟩. ⟨hal-03808039⟩
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