Department of Pathology, University of Cambridge, Cambridge, UK.
Medical Research Council Cancer Unit, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK.
J Cell Biol. 2022 Jul 4;221(7). doi: 10.1083/jcb.202203095. Epub 2022 Jun 7.
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.
Fbxo7 与癌症和帕金森病有关。虽然 Fbxo7 将底物募集到 SCF 型泛素连接酶中，但它也以非连接酶依赖的方式促进 Cdk6 的激活。我们在筛选 Fbxo7 底物时发现了糖酵解的守门员 PFKP。PFKP 是某些 T-ALL 细胞中 Cdk6 的必需底物。我们研究了 Fbxo7、Cdk6 和 PFKP 之间的分子关系，以及 Fbxo7 对 T 细胞代谢、活力和激活的影响。Fbxo7 促进 PFKP 的 Cdk6 非依赖性泛素化和 Cdk6 依赖性磷酸化。重要的是，缺乏 Fbxo7 的细胞中 Cdk6 活性降低，造血和淋巴细胞表达水平高，对 Fbxo7 有明显的依赖性。Fbxo7 减少的 CD4+T 细胞表现出增加的糖酵解作用，尽管细胞活力和激活水平较低。激活的 CD4+T 细胞的代谢组学研究证实，缺乏 Fbxo7 的细胞中糖酵解通量增加，同时核苷酸生物合成和精氨酸代谢发生改变。我们表明 Fbxo7 在 mRNA 和蛋白质水平上对葡萄糖有反应性，并提出 Fbxo7 通过激活 Cdk6 抑制 PFKP 和糖酵解。
