A role for O-GlcNAcylation in setting circadian clock speed
A role for O-GlcNAcylation in setting circadian clock speed
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DOI：
10.1101/gad.182378.111
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发表时间：
2012-03-01
影响因子：
10.5
通讯作者：
Cho, Jin Won
中科院分区：
文献类型：
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作者：
Kim, Eun Young;Jeong, Eun Hee;Cho, Jin Won
一种或多种中央“时钟”蛋白的翻译后修饰，最显着的是磷酸化的一天中时间依赖性变化，对于设定昼夜节律（与 24 小时一致）时钟的节奏至关重要。在动物中，PERIOD (PER) 蛋白是调节昼夜节律时钟速度的关键状态变量，并经历丰度和细胞质-核分布的日常变化，部分由复杂的驱动 磷酸化程序。在这里，我们将 O-GlcNAc 确定为昼夜节律调节中的关键翻译后修饰，也有助于设置时钟速度。时钟细胞中果蝇 O-GlcNAc 转移酶 (ogt) 的敲低或过度表达分别会缩短或延长昼夜行为节律。果蝇 PERIOD 蛋白 (dPER) 是 OGT 和 O-GlcNAcylation 每天都会发生变化，这种修饰主要在前半夜观察到，此时 dPER 主要位于细胞质中。有趣的是，果蝇中 dPER 从细胞质转移到细胞核的时间提前或延迟，其中 ogt 表达分别减少或增加。我们的结果表明 O-GlcNAc 酰化 dPER 通过延迟 dPER 进入核的时间来帮助设定正确的时钟速度。此外，OGT 可以稳定 dPER，这表明 O-GlcNAc 酰化在昼夜节律计时系统中具有多种作用。
Post-translational modifications of one or more central "clock'' proteins, most notably time-of-day-dependent changes in phosphorylation, are critical for setting the pace of circadian (congruent to 24 h) clocks. In animals, PERIOD (PER) proteins are the key state variable regulating circadian clock speed and undergo daily changes in abundance and cytoplasmic-nuclear distribution that are partly driven by a complex phosphorylation program. Here, we identify O-GlcNAcylation (O-GlcNAc) as a critical post-translational modification in circadian regulation that also contributes to setting clock speed. Knockdown or overexpression of Drosophila O-GlcNAc transferase (ogt) in clock cells either shortens or lengthens circadian behavioral rhythms, respectively. The Drosophila PERIOD protein (dPER) is a direct target of OGT and undergoes daily changes in O-GlcNAcylation, a modification that is mainly observed during the first half of the night, when dPER is predominantly located in the cytoplasm. Intriguingly, the timing of when dPER translocates from the cytoplasm to the nucleus is advanced or delayed in flies, wherein ogt expression is reduced or increased, respectively. Our results suggest that O-GlcNAcylation of dPER contributes to setting the correct pace of the clock by delaying the timing of dPER nuclear entry. In addition, OGT stabilizes dPER, suggesting that O-GlcNAcylation has multiple roles in circadian timing systems.