| First Author | Harris R | Year | 2022 |
| Journal | J Cell Biol | Volume | 221 |
| Issue | 7 | PubMed ID | 35670764 |
| Mgi Jnum | J:328648 | Mgi Id | MGI:7285846 |
| Doi | 10.1083/jcb.202203095 | Citation | Harris R, et al. (2022) Fbxo7 promotes Cdk6 activity to inhibit PFKP and glycolysis in T cells. J Cell Biol 221(7):e202203095 |
| abstractText | 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. |
