Paradoski Brandon T, Hou Sen, Mejia Edgard M, Olayinka-Adefemi Folayemi, Fowke Danielle, Hatch Grant M, Saleem Ayesha, Banerji Versha, Hay Nissim, Zeng Hu, Marshall Aaron J
Departments of Immunology, University of Manitoba, Winnipeg, Canada.
Pharmacology and Therapeutics, University of Manitoba, Winnipeg, Canada.
iScience. 2024 Sep 13;27(10):110939. doi: 10.1016/j.isci.2024.110939. eCollection 2024 Oct 18.
B lymphocyte activation triggers metabolic reprogramming essential for B cell differentiation and mounting a healthy immune response. Here, we investigate the regulation and function of glucose-phosphorylating enzyme hexokinase 2 (HK2) in B cells. We report that both activation-dependent expression and mitochondrial localization of HK2 are regulated by the phosphatidylinositol 3-kinase (PI3K) signaling pathway. B cell-specific deletion of HK2 in mice caused mild perturbations in B cell development. HK2-deficient B cells show impaired functional responses and adapt to become less dependent on glucose and more dependent on glutamine. HK2 deficiency impairs glycolysis, alters metabolite profiles, and alters flux of labeled glucose carbons into downstream pathways. Upon immunization, HK2-deficient mice exhibit impaired germinal center, plasmablast, and antibody responses. HK2 expression in primary human chronic lymphocytic leukemia (CLL) cells was associated with recent proliferation and could be reduced by PI3K inhibition. Our study implicates PI3K-dependent modulation of HK2 in B cell metabolic reprogramming.
B淋巴细胞激活引发代谢重编程，这对B细胞分化和产生健康的免疫反应至关重要。在此，我们研究了葡萄糖磷酸化酶己糖激酶2（HK2）在B细胞中的调节作用和功能。我们报告称，HK2的激活依赖性表达和线粒体定位均受磷脂酰肌醇3激酶（PI3K）信号通路调控。小鼠B细胞特异性缺失HK2会导致B细胞发育出现轻微紊乱。HK2缺陷型B细胞显示出功能反应受损，并适应减少对葡萄糖的依赖，增加对谷氨酰胺的依赖。HK2缺陷会损害糖酵解，改变代谢物谱，并改变标记葡萄糖碳进入下游途径的通量。免疫后，HK2缺陷型小鼠的生发中心、浆母细胞和抗体反应受损。原发性人类慢性淋巴细胞白血病（CLL）细胞中的HK2表达与近期增殖相关，并且可通过PI3K抑制作用降低。我们的研究表明PI3K对HK2的依赖性调节参与了B细胞代谢重编程。
