Housley Michael P, Rodgers Joseph T, Udeshi Namrata D, Kelly Timothy J, Shabanowitz Jeffrey, Hunt Donald F, Puigserver Pere, Hart Gerald W
Department of Biological Chemistry, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
J Biol Chem. 2008 Jun 13;283(24):16283-92. doi: 10.1074/jbc.M802240200. Epub 2008 Apr 17.
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.
FoxO蛋白是营养稳态和应激反应的关键转录调节因子。转录因子FoxO1可激活包括磷酸烯醇式丙酮酸羧激酶和葡萄糖-6-磷酸酶在内的糖异生相关基因的表达，还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进行的激素和应激依赖性调节已得到充分证实，但尚未在葡萄糖衍生的O-连接β-N-乙酰葡糖胺（O-GlcNAc）修饰的背景下对FoxOs进行研究。在此我们表明，糖尿病时肝脏中FoxO1上的O-GlcNAc会增加。此外，O-GlcNAc可调节FoxO1对葡萄糖的反应性激活，导致糖异生基因的表达反常增加，同时诱导编码可清除活性氧的酶的基因表达。FoxO的O-GlcNAc化提供了一种直接通过营养物质控制转录的新机制，通过控制FoxO1的活性来调节代谢和应激反应。
