KPNB1 mediates PER/CRY nuclear translocation and circadian clock function.
KPNB1 mediates PER/CRY nuclear translocation and circadian clock function.
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DOI：
10.7554/elife.08647
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发表时间：
2015-08-29
期刊：
影响因子：
7.7
通讯作者：
Hogenesch JB
中科院分区：
文献类型：
--
作者：
Lee Y;Jang AR;Francey LJ;Sehgal A;Hogenesch JB
PER/CRY阻遏蛋白复合物的核转位对哺乳动物生物钟的负反馈调节至关重要。然而，精确的分子机制尚未完全理解。本文报道了活化T细胞核因子（NRON）核糖核蛋白复合物ncRNA阻遏物的输入素β组分KPNB 1介导PER/CRY复合物的核转位和阻遏物功能。KPNB 1的RNAi耗尽通过阻止人类细胞中PER蛋白的核进入来将PER/CRY复合物捕获在细胞质中。KPNB 1主要与PER蛋白相互作用，并以昼夜节律的方式指导PER/CRY核转运。有趣的是，KPNB 1调节PER/CRY核进入和阻遏物功能，独立于其经典伴侣importin α。此外，在侧神经元中保守的果蝇importin β的可诱导抑制消除了果蝇的行为节律。总的来说，这些数据表明，KPNB 1需要在昼夜节律钟的负反馈调节中及时输入PER/CRY。http://dx.doi.org/10.7554/eLife.08647.001大多数生物体都有一个内部时钟--被称为生物钟--它以大约24小时的周期来调节生物学和行为的许多方面。在动物中，生物钟的核心是由两种“激活”蛋白和两种“抑制”蛋白组成，它们抑制激活剂，因此细胞中所有四种蛋白的水平在周期中波动。激活蛋白开启编码阻遏蛋白的基因。这增加了阻遏蛋白在细胞质中的产量。然后阻遏蛋白相互结合，然后进入细胞核，以抑制激活蛋白。然而，目前尚不清楚阻遏蛋白如何进入细胞核。Lee等人使用一种称为“RNA干扰”的技术来研究人类细胞和果蝇的生物钟。实验表明，一种名为importin β的蛋白质能够使阻遏蛋白进入细胞核。Importin β仅与一种阻遏蛋白（称为PER）直接相互作用。以前的研究表明，importin β能够与另一种称为importin α的蛋白质相互作用，但Lee et al.的结果表明，这种相互作用对importin β在阻遏蛋白运动中的作用并不重要。阻断importin β的活性会导致人类细胞和果蝇的昼夜节律丧失，这表明importin β在许多不同的动物中发挥相同的作用。生物钟在许多癌症中被打乱，所以Lee et al.的发现也可能有助于引导我们找到对抗这些疾病的新疗法。DOI：http://dx.doi.org/10.7554/eLife.08647.002网站
Regulated nuclear translocation of the PER/CRY repressor complex is critical for negative feedback regulation of the circadian clock of mammals. However, the precise molecular mechanism is not fully understood. Here, we report that KPNB1, an importin β component of the ncRNA repressor of nuclear factor of activated T cells (NRON) ribonucleoprotein complex, mediates nuclear translocation and repressor function of the PER/CRY complex. RNAi depletion of KPNB1 traps the PER/CRY complex in the cytoplasm by blocking nuclear entry of PER proteins in human cells. KPNB1 interacts mainly with PER proteins and directs PER/CRY nuclear transport in a circadian fashion. Interestingly, KPNB1 regulates the PER/CRY nuclear entry and repressor function, independently of importin α, its classical partner. Moreover, inducible inhibition of the conserved Drosophila importin β in lateral neurons abolishes behavioral rhythms in flies. Collectively, these data show that KPNB1 is required for timely nuclear import of PER/CRY in the negative feedback regulation of the circadian clock. DOI: http://dx.doi.org/10.7554/eLife.08647.001 Most organisms have an internal clock—known as the circadian clock—that regulates many aspects of their biology and behavior in roughly 24-hr long cycles. In animals, the core of the circadian clock is made of two ‘activator’ proteins and two ‘repressor’ proteins that inhibit the activators so that the levels of all four proteins in cells fluctuate over the cycle. The activator proteins switch on the genes that encode the repressor proteins. This increases the production of the repressor proteins in an area of the cell called the cytoplasm. The repressor proteins then bind to each other and then move into the nucleus of the cell to inactivate the activator proteins. However, it was not clear how the repressor proteins move into the nucleus. Lee et al. used a technique called ‘RNA interference’ to study the circadian clock in human cells and fruit flies. The experiments show that a protein called importin β enables the repressor proteins to move into the nucleus. Importin β directly interacted with only one of the repressor proteins (called PER). Previous studies have shown that importin β is able to interact with another protein called importin α, but Lee et al.'s results show that this interaction is not important for importin β's role in the movement of the repressor proteins. Blocking importin β activity resulted in the loss of circadian rhythms in both human cells and fruit flies, which suggests that importin β performs the same role in many different animals. The circadian clock is disrupted in many cancers, so Lee et al.'s findings may also help to lead us to new treatments to fight these diseases. DOI: http://dx.doi.org/10.7554/eLife.08647.002