A PGC-1α-O-GlcNAc Transferase Complex Regulates FoxO Transcription Factor Activity in Response to Glucose
A PGC-1α-O-GlcNAc Transferase Complex Regulates FoxO Transcription Factor Activity in Response to Glucose
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DOI：
10.1074/jbc.m808890200
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发表时间：
2009-02-20
影响因子：
4.8
通讯作者：
Hart, Gerald W.
中科院分区：
文献类型：
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作者：
Housley, Michael P.;Udeshi, Namrata D.;Hart, Gerald W.
代谢和应激反应基因调控是生物体在不断变化的环境中生存的关键。感知营养物质并广泛影响基因表达的三个关键分子是FoxO转录因子、转录共激活因子PGC-1 α和翻译后动态修饰O-linked β - n -乙酰氨基葡萄糖（O-GlcNAc）。在这里，我们发现了PGC-1 α的新的翻译后修饰，包括O-GlcNAc，并描述了PGC-1 α如何通过FoxOs共同激活转录的新机制。在肝脏、培养细胞和体外重组蛋白中，PGC-1 α与O-GlcNAc转移酶结合，并将该酶靶向FoxOs，导致其glcnac酰化和转录活性增加。此外，葡萄糖增强fox01的激活通过PGC-1 α - o - glcnac转移酶介导的glcnac酰化发生。因此，PGC-1 α作为转录共激活因子的一种机制是通过靶向O-GlcNAc转移酶来增加对营养/应激感知和能量代谢重要的特定转录因子的glcn酰化。
Metabolic and stress response gene regulation is crucial for the survival of an organism to a changing environment. Three key molecules that sense nutrients and broadly affect gene expression are the FoxO transcription factors, the transcriptional co-activator PGC-1 alpha, and the dynamic post-translational modification, O-linked beta-N-acetylglucosamine (O-GlcNAc). Here we identify novel post-translational modifications of PGC-1 alpha, including O-GlcNAc, and describe a novel mechanism for how PGC-1 alpha co-activates transcription by FoxOs. In liver, in cultured cells, and in vitro with recombinant proteins, PGC-1 alpha binds to O-GlcNAc transferase and targets the enzyme to FoxOs, resulting in their increased GlcNAcylation and increased transcriptional activity. Furthermore, glucose-enhanced activation of FoxO1 occurs via this PGC-1 alpha-O-GlcNAc transferase-mediated GlcNAcylation. Therefore, one mechanism by which PGC-1 alpha can serve as a co-activator of transcription is by targeting the O-GlcNAc transferase to increase GlcNAcylation of specific transcription factors important to nutrient/stress sensing and energy metabolism.