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首页> 外文期刊>Cell metabolism >O-GlcNAc signaling entrains the circadian clock by inhibiting BMAL1/CLOCK ubiquitination
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O-GlcNAc signaling entrains the circadian clock by inhibiting BMAL1/CLOCK ubiquitination

机译：O-GlcNAc信号传导通过抑制BMAL1 / CLOCK泛素化而带动昼夜节律

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摘要

Circadian clocks are coupled to metabolic oscillations through nutrient-sensing pathways. Nutrient flux into the hexosamine biosynthesis pathway triggers covalent protein modification by O-linked β-D-N- acetylglucosamine (O-GlcNAc). Here we show that the hexosamine/O-GlcNAc pathway modulates peripheral clock oscillation. O-GlcNAc transferase (OGT) promotes expression of BMAL1/CLOCK target genes and affects circadian oscillation of clock genes in vitro and in vivo. Both BMAL1 and CLOCK are rhythmically O-GlcNAcylated, and this protein modification stabilizes BMAL1 and CLOCK by inhibiting their ubiquitination. In vivo analysis of genetically modified mice with perturbed hepatic OGT expression shows aberrant circadian rhythms of glucose homeostasis. These results establish the counteraction between O-GlcNAcylation and ubiquitination as a key mechanism that regulates the circadian clock and suggest a crucial role for O-GlcNAc signaling in transducing nutritional signals to the core circadian timing machinery.
机译：昼夜节律钟通过营养感应途径与代谢振荡耦合。进入六胺生物合成途径的养分通量可通过O-连接的β-D-N-乙酰氨基葡萄糖（O-GlcNAc）触发共价蛋白修饰。在这里，我们显示了六胺/ O-GlcNAc途径调节外围时钟振荡。 O-GlcNAc转移酶（OGT）促进BMAL1 / CLOCK靶基因的表达，并在体外和体内影响时钟基因的昼夜节律振荡。 BMAL1和CLOCK都在节奏上被O-GlcNAcy酰化，这种蛋白质修饰通过抑制它们的泛素化作用来稳定BMAL1和CLOCK。对肝OGT表达受到干扰的转基因小鼠的体内分析显示，葡萄糖稳态的昼夜节律异常。这些结果建立了O-GlcNAcy酰化和泛素化之间的反作用，这是调节生物钟的关键机制，并暗示了O-GlcNAc信号在将营养信号转导至生物钟定时机制中的关键作用。

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