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

Rebecca Harris, Ming Yang, Christina Schmidt, Chloe Royet, Sarbjit Singh, Amarnath Natarajan, May Morris, Christian Frezza, Heike Laman

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

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 Cdk6independent 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.

Original languageEnglish (US)
Article numbere202203095
JournalJournal of Cell Biology
Volume221
Issue number7
DOIs
StatePublished - Jul 4 2022

ASJC Scopus subject areas

  • Cell Biology

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