The rate of glycolysis quantitatively mediates specific histone acetylation sites.
The rate of glycolysis quantitatively mediates specific histone acetylation sites.
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DOI：
10.1186/s40170-015-0135-3
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发表时间：
2015
影响因子：
5.9
通讯作者：
Locasale JW
中科院分区：
文献类型：
--
作者：
Cluntun AA;Huang H;Dai L;Liu X;Zhao Y;Locasale JW
葡萄糖代谢将代谢状态与蛋白质乙酰化联系起来。然而，人们对葡萄糖代谢特征在多大程度上促进蛋白质乙酰化以及该过程是否可以通过不同的糖酵解速率进行动态和定量调节仍然知之甚少。在这里，我们表明，糖酵解的可滴定速率以及糖酵解中间体水平的相应变化会导致大部分代谢组的分级重塑，并导致总组蛋白乙酰化水平的逐渐变化。我们发现动态组蛋白乙酰化水平与乙酰辅酶 A (ac-CoA) 水平密切相关，并且与 ac-CoA 与游离 CoA 的比率呈负相关。基于细胞培养中氨基酸的多重稳定同位素标记 (SILAC) 的蛋白质组学方法表明，一半已识别的组蛋白乙酰化位点以及其他赖氨酸酰化修饰的水平通过糖酵解速率进行调节，表明糖酵解速率影响特定的酰化位点。我们证明，组蛋白酰化是通过葡萄糖流以可滴定的、剂量依赖性的方式直接感知的，该方式由糖酵解流调节，并且瓦伯格效应（在葡萄糖代谢增强的癌症中观察到的一种代谢状态）的可能功能是赋予细胞特定的信号传导效应。
Glucose metabolism links metabolic status to protein acetylation. However, it remains poorly understood to what extent do features of glucose metabolism contribute to protein acetylation and whether the process can be dynamically and quantitatively regulated by differing rates of glycolysis. Here, we show that titratable rates of glycolysis with corresponding changes in the levels of glycolytic intermediates result in a graded remodeling of a bulk of the metabolome and resulted in gradual changes in total histone acetylation levels. Dynamic histone acetylation levels were found and most strongly correlated with acetyl coenzyme A (ac-CoA) levels and inversely associated with the ratio of ac-CoA to free CoA. A multiplexed stable isotopic labeling by amino acids in cell culture (SILAC)-based proteomics approach revealed that the levels of half of identified histone acetylation sites as well as other lysine acylation modifications are tuned by the rate of glycolysis demonstrating that glycolytic rate affects specific acylation sites. We demonstrate that histone acylation is directly sensed by glucose flux in a titratable, dose-dependent manner that is modulated by glycolytic flux and that a possible function of the Warburg Effect, a metabolic state observed in cancers with enhanced glucose metabolism, is to confer specific signaling effects on cells.