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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Glutamine-dependent anapleurosis dictates glucose uptake and cell growth by regulating MondoA transcriptional activity
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Glutamine-dependent anapleurosis dictates glucose uptake and cell growth by regulating MondoA transcriptional activity

机译：谷氨酰胺依赖性小动脉瘤病通过调节MondoA转录活性决定葡萄糖的摄取和细胞生长

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Glucose and glutamine are abundant nutrients required for cell growth, yet how cells sense and adapt to changes in their levels is not well understood. The MondoA transcription factor forms a heterocomplex with its obligate partner Mlx to regulate ≈75% of glucose-dependent transcription. By mediating glucose-induced activation of thioredoxin-interacting protein (TXNIP), MondoA:Mlx complexes directly repress glucose uptake. We show here that glutamine inhibits transcriptional activation of TXNIP by triggering the recruitment of a histone deacetylase-dependent corepressor to the amino terminus of MondoA. Therefore, in the presence of both glucose and glutamine, TXNIP expression is low, which favors glucose uptake and aerobic glycolysis; the Warburg effect. Consistent with MondoA functioning upstream of TXNIP, MondoA knockdown reduces TXNIP expression, elevates glucose uptake and stimulates cell proliferation. Although glutamine has many intracellular fates, a cell permeable analog of a tricarboxylic acid cycle (TCA) intermediate, α-ketoglutarate, also blocks the transcriptional activity of MondoA at the TXNIP promoter and stimulates glucose uptake. Together our data suggest that glutamine-dependent mitochondrial anapleurosis dictates glucose uptake and aerobic glycolysis by blocking MondoA:Mlx-dependent transcriptional activation of TXNIP. We propose that this previously unappreciated coordination between glutamine and glucose utilization defines a metabolic checkpoint that restricts cell growth when subthreshold levels of these essential nutrients are available.
机译：葡萄糖和谷氨酰胺是细胞生长所需的丰富营养素，但是人们对细胞如何感知和适应其水平变化的了解还不清楚。 MondoA转录因子与其专职的伴侣Mlx形成异源复合物，以调节约75％的葡萄糖依赖性转录。通过介导葡萄糖诱导的硫氧还蛋白相互作用蛋白（TXNIP）的激活，MondoA：Mlx复合物直接抑制了葡萄糖的摄取。我们在这里显示，谷氨酰胺通过触发组蛋白脱乙酰基酶依赖的corepressor募集到MondoA的氨基末端来抑制TXNIP的转录激活。因此，在同时存在葡萄糖和谷氨酰胺的情况下，TXNIP表达低，这有利于葡萄糖摄取和有氧糖酵解。沃堡效应。与在TXNIP上游起作用的MondoA一致，MondoA敲低可降低TXNIP表达，提高葡萄糖摄取并刺激细胞增殖。尽管谷氨酰胺具有许多细胞内命运，但三羧酸循环（TCA）中间体的细胞可渗透类似物α-酮戊二酸也可阻断MondoA在TXNIP启动子上的转录活性并刺激葡萄糖吸收。在一起我们的数据表明，谷氨酰胺依赖性线粒体不全症通过阻断TXNIP的MondoA：Mlx依赖性转录激活来决定葡萄糖的摄取和有氧糖酵解。我们建议，谷氨酰胺和葡萄糖利用之间这种先前未曾认识到的协调作用定义了一个代谢检查点，当这些基本营养素的亚阈值水平可用时，该检查点会限制细胞的生长。

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