Glucose sensor O-GlcNAcylation coordinates with phosphorylation to regulate circadian clock.
Glucose sensor O-GlcNAcylation coordinates with phosphorylation to regulate circadian clock.
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DOI：
10.1016/j.cmet.2012.12.017
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发表时间：
2013-02-05
期刊：
影响因子：
29
通讯作者：
Fu YH
中科院分区：
文献类型：
--
作者：
Kaasik K;Kivimäe S;Allen JJ;Chalkley RJ;Huang Y;Baer K;Kissel H;Burlingame AL;Shokat KM;Ptáček LJ;Fu YH
翻译后修饰在包括昼夜节律调节在内的无数生物学途径中起着核心作用。我们采用昼夜蛋白质组学方法证明磷酸化的昼夜时间是调节复杂的GSK 3 β依赖性途径的关键因素，并鉴定了O-GlcNAc转移酶（OGT）作为GSK 3 β的底物。有趣的是，OGT活性受GSK 3 β调节，因此OGT和GSK 3 β表现出相互调节。调节OGlcNAc化水平改变小鼠和果蝇的昼夜节律周期长度，相反，蛋白质O-GlcNAc化受到昼夜节律调节。中心时钟蛋白Clock和Period通过O-GlcNAcylation可逆地修饰以调节其转录活性。此外，已知调节人类睡眠期（S662-S674）的PER 2区域的O-GlcNAc化与该区域的磷酸化竞争，并且这种相互作用至少部分地由葡萄糖水平介导。总之，这些结果表明，O-GlcNAc酰化作为生物钟调节的代谢传感器，并与磷酸化协同工作，以微调昼夜节律钟。
Post-translational modifications play central roles in myriad biological pathways including circadian regulation. We employed a circadian proteomic approach to demonstrate that circadian timing of phosphorylation is a critical factor in regulating complex GSK3β dependent pathways and identified O-GlcNAc transferase (OGT) as a substrate of GSK3β. Interestingly, OGT activity is regulated by GSK3β, hence OGT and GSK3β exhibit reciprocal regulation. Modulating OGlcNAcylation levels alter circadian period length in both mice and Drosophila, and conversely protein O-GlcNAcylation is circadianly regulated. Central clock proteins, Clock and Period, are reversibly modified by O-GlcNAcylation to regulate their transcriptional activities. In addition, O-GlcNAcylation of a region in PER2 known to regulate human sleep phase (S662–S674) competes with phosphorylation of this region, and this interplay is at least partly mediated by glucose levels. Together, these results indicate that O-GlcNAcylation serves as a metabolic sensor for clock regulation and works coordinately with phosphorylation to fine tune circadian clock.
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影响因子：
64.5
作者：
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通讯作者：
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影响因子：
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作者：
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影响因子：
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作者：
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DOI：
10.1073/pnas.0811410106
发表时间：
2008-12-30
影响因子：
11.1
作者：
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通讯作者：
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