Araujo Lindsey, Khim Phillip, Mkhikian Haik, Mortales Christie-Lynn, Demetriou Michael
Department of Microbiology and Molecular Genetics, University of California, Irvine, United States.
Department of Neurology and Institute for Immunology, University of California, Irvine, United States.
Elife. 2017 Jan 6;6:e21330. doi: 10.7554/eLife.21330.
Rapidly proliferating cells switch from oxidative phosphorylation to aerobic glycolysis plus glutaminolysis, markedly increasing glucose and glutamine catabolism. Although Otto Warburg first described aerobic glycolysis in cancer cells >90 years ago, the primary purpose of this metabolic switch remains controversial. The hexosamine biosynthetic pathway requires glucose and glutamine for de novo synthesis of UDP-GlcNAc, a sugar-nucleotide that inhibits receptor endocytosis and signaling by promoting N-acetylglucosamine branching of Asn (N)-linked glycans. Here, we report that aerobic glycolysis and glutaminolysis co-operatively reduce UDP-GlcNAc biosynthesis and N-glycan branching in mouse T cell blasts by starving the hexosamine pathway of glucose and glutamine. This drives growth and pro-inflammatory T17 over anti-inflammatory-induced T regulatory (iTreg) differentiation, the latter by promoting endocytic loss of IL-2 receptor-α (CD25). Thus, a primary function of aerobic glycolysis and glutaminolysis is to co-operatively limit metabolite supply to N-glycan biosynthesis, an activity with widespread implications for autoimmunity and cancer.
快速增殖的细胞从氧化磷酸化转变为有氧糖酵解加谷氨酰胺分解代谢，显著增加葡萄糖和谷氨酰胺的分解代谢。尽管奥托·瓦尔堡在90多年前首次描述了癌细胞中的有氧糖酵解，但这种代谢转换的主要目的仍存在争议。己糖胺生物合成途径需要葡萄糖和谷氨酰胺来从头合成UDP-GlcNAc，这是一种糖核苷酸，通过促进天冬酰胺（N）连接聚糖的N-乙酰葡糖胺分支来抑制受体胞吞作用和信号传导。在这里，我们报告有氧糖酵解和谷氨酰胺分解代谢通过使己糖胺途径缺乏葡萄糖和谷氨酰胺，协同降低小鼠T细胞母细胞中UDP-GlcNAc的生物合成和N-聚糖分支。这驱动了生长以及促炎T17细胞相对于抗炎诱导的调节性T细胞（iTreg）分化的优势，后者是通过促进IL-2受体α（CD25）的内吞性丧失实现的。因此，有氧糖酵解和谷氨酰胺分解代谢的一个主要功能是协同限制代谢物供应给N-聚糖生物合成，这一活动对自身免疫和癌症具有广泛影响。
