O-GlcNAc regulates FoxO activation in response to glucose
O-GlcNAc regulates FoxO activation in response to glucose
复制标题
DOI：
10.1074/jbc.m802240200
复制
发表时间：
2008-06-13
影响因子：
4.8
通讯作者：
Hart, Gerald W.
中科院分区：
文献类型：
--
作者：
Housley, Michael P.;Rodgers, Joseph T.;Hart, Gerald W.
FOXO蛋白是营养动态平衡和胁迫反应的关键转录调节因子。转录因子FoxO1可激活葡萄糖异生蛋白的表达，包括磷酸烯醇式丙酮酸羧酸激酶和葡萄糖-6-磷酸酶，也可激活氧化应激反应酶过氧化氢酶和锰超氧化物歧化酶的表达。通过乙酰化、泛素化和磷酸化对FoxO1进行激素和应激依赖的调节已经得到了很好的证实，但FoxOS还没有在葡萄糖衍生的O-连接的β-N-乙酰氨基葡萄糖(O-GlcNAc)修饰的背景下进行研究。在这里，我们显示O-GlcNAc对肝脏FoxO1的作用在糖尿病时增加。此外，O-GlcNAc调节FoxO1对葡萄糖的响应，导致糖异生基因的表达反常地增加，同时诱导编码酶的基因的表达，从而使活性氧物种解毒。FoxO的GlcN酰化为直接营养调控转录提供了一种新的机制，通过控制FoxO1活性来调节新陈代谢和应激反应。
FoxO proteins are key transcriptional regulators of nutrient homeostasis and stress response. The transcription factor FoxO1 activates expression of gluconeogenic, including phosphoenolpyruvate carboxykinase and glucose-6-phosphatase, and also activates the expression of the oxidative stress response enzymes catalase and manganese superoxide dismutase. Hormonal and stress-dependent regulation of FoxO1 via acetylation, ubiquitination, and phosphorylation, are well established, but FoxOs have not been studied in the context of the glucose-derived O-linked beta-N-acetylglucosamine (O-GlcNAc) modification. Here we show that O-GlcNAc on hepatic FoxO1 is increased in diabetes. Furthermore, O-GlcNAc regulates FoxO1 activation in response to glucose, resulting in the paradoxically increased expression of gluconeogenic genes while concomitantly inducing expression of genes encoding enzymes that detoxify reactive oxygen species. GlcNAcylation of FoxO provides a new mechanism for direct nutrient control of transcription to regulate metabolism and stress response through control of FoxO1 activity.