The hexosamine biosynthetic pathway couples growth factor-induced glutamine uptake to glucose metabolism
The hexosamine biosynthetic pathway couples growth factor-induced glutamine uptake to glucose metabolism
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DOI：
10.1101/gad.1985910
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发表时间：
2010-12-15
影响因子：
10.5
通讯作者：
Thompson, Craig B.
中科院分区：
文献类型：
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作者：
Wellen, Kathryn E.;Lu, Chao;Thompson, Craig B.
葡萄糖和谷氨酰胺作为增殖细胞中的两种主要碳源，并且这两种营养素的摄取由生长因子信号传导指导。虽然葡萄糖或谷氨酰胺可以潜在地支持线粒体三羧酸（TCA）循环的完整性和ATP的生产，我们发现，葡萄糖剥夺导致谷氨酰胺摄取显着减少和进行性细胞萎缩在多种哺乳动物细胞类型。尽管生长因子的持续存在和细胞外谷氨酰胺的丰富供应，白细胞介素-3（IL-3）依赖性细胞无法维持TCA循环代谢物池或受体依赖性信号转导时，剥夺葡萄糖。这至少部分是由于在不存在葡萄糖的情况下IL-3受体α（IL-3R α）表面表达的下调。用N-乙酰葡糖胺（GlcNAc）处理葡萄糖饥饿的细胞以维持己糖胺生物合成，通过促进IL-3依赖性谷氨酰胺摄取和代谢恢复线粒体代谢和细胞生长。因此，需要通过己糖胺生物合成途径的葡萄糖代谢来维持足够的生长因子信号传导和谷氨酰胺摄取以支持细胞生长和存活。
Glucose and glutamine serve as the two primary carbon sources in proliferating cells, and uptake of both nutrients is directed by growth factor signaling. Although either glucose or glutamine can potentially support mitochondrial tricarboxylic acid (TCA) cycle integrity and ATP production, we found that glucose deprivation led to a marked reduction in glutamine uptake and progressive cellular atrophy in multiple mammalian cell types. Despite the continuous presence of growth factor and an abundant supply of extracellular glutamine, interleukin-3 (IL-3)-dependent cells were unable to maintain TCA cycle metabolite pools or receptor-dependent signal transduction when deprived of glucose. This was due at least in part to down-regulation of IL-3 receptor alpha (IL-3R alpha) surface expression in the absence of glucose. Treatment of glucose-starved cells with N-acetylglucosamine (GlcNAc) to maintain hexosamine biosynthesis restored mitochondrial metabolism and cell growth by promoting IL-3-dependent glutamine uptake and metabolism. Thus, glucose metabolism through the hexosamine biosynthetic pathway is required to sustain sufficient growth factor signaling and glutamine uptake to support cell growth and survival.