Glycolysis and glutaminolysis cooperatively control T cell function by limiting metabolite supply to N-glycosylation
Glycolysis and glutaminolysis cooperatively control T cell function by limiting metabolite supply to N-glycosylation
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DOI：
10.7554/elife.21330
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发表时间：
2017-01-06
期刊：
影响因子：
7.7
通讯作者：
Demetriou, Michael
中科院分区：
文献类型：
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作者：
Araujo, Lindsey;Khim, Phillip;Demetriou, Michael
快速增殖的细胞从氧化磷酸化转变为有氧糖酵解加谷氨酸解，显著增加葡萄糖和谷氨酰胺催化剂。虽然奥托瓦尔堡第一次描述有氧糖酵解在癌细胞>90年前，这种代谢开关的主要目的仍然存在争议。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，UDP-GlcNAc是一种通过促进Asn（N）连接聚糖的N-乙酰葡糖胺分支来抑制受体内吞作用和信号传导的糖核苷酸。在这里，我们报告有氧糖酵解和氨解合作减少UDP-GlcNAc生物合成和N-聚糖分支小鼠T细胞母细胞饥饿的葡萄糖和谷氨酰胺的己糖胺途径。这驱动生长和促炎T（H）17超过抗炎诱导的T调节（iTreg）分化，后者通过促进IL-2受体-α（CD 25）的内吞损失。因此，需氧糖酵解和氨解的主要功能是协同限制N-聚糖生物合成的代谢物供应，这是一种对自身免疫和癌症具有广泛影响的活性。
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 T(H)17 over anti-inflammatory-induced T regulatory (iTreg) differentiation, the latter by promoting endocytic loss of IL-2 receptor-alpha (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.