FBXL21 Regulates Oscillation of the Circadian Clock through Ubiquitination and Stabilization of Cryptochromes
FBXL21 Regulates Oscillation of the Circadian Clock through Ubiquitination and Stabilization of Cryptochromes
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DOI：
10.1016/j.cell.2013.01.054
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发表时间：
2013-02-28
期刊：
影响因子：
64.5
通讯作者：
Fukada, Yoshitaka
中科院分区：
文献类型：
--
作者：
Hirano, Arisa;Yumimoto, Kanae;Fukada, Yoshitaka
在哺乳动物的昼夜节律时钟系统中，生物钟基因的翻译后修饰调节了阻遏蛋白G11和G12的转录。先前的研究表明FBXL 3是一种F-box-type E3连接酶，可泛素化β-淀粉样蛋白并介导其降解。在这里，我们发现FBXL 21也泛素化β，但抵消FBXL 3。Fbxl 21（-/-）小鼠表现出正常的轮跑节律周期性，日常活动的组织受损，而Fbxl 3（-/-）小鼠的极长周期表型在Fbxl 3/Fbxl 21双敲除小鼠中减弱。双敲除使行为节律逐渐不稳定，有时会引起不稳定性。令人惊讶的是，FBXL 21稳定化了细胞并拮抗了FBXL 3的去稳定作用。FBXL 21的主要胞质分布与FBXL 3的核定位形成对比。这些结果强调了FBXL 21和FBXL 3之间拮抗作用对生物钟的生理重要性，并且它们在不同亚细胞位置的联合作用稳定了生物钟的振荡。
In the mammalian circadian clockwork, CRY1 and CRY2 repressor proteins are regulated by posttranslational modifications for temporally coordinated transcription of clock genes. Previous studies revealed that FBXL3, an F-box-type E3 ligase, ubiquitinates CRYs and mediates their degradation. Here, we found that FBXL21 also ubiquitinates CRYs but counteracts FBXL3. Fbxl21(-/-) mice exhibited normal periodicity of wheel-running rhythms with compromised organization of daily activities, while an extremely long-period phenotype of Fbxl3(-/-) mice was attenuated in Fbxl3/Fbxl21 double-knockout mice. The double knockout destabilized the behavioral rhythms progressively and sometimes elicited arrhythmicity. Surprisingly, FBXL21 stabilized CRYs and antagonized the destabilizing action by FBXL3. Predominantly cytosolic distribution of FBXL21 contrasts with nuclear localization of FBXL3. These results emphasize the physiological importance of antagonizing actions between FBXL21 and FBXL3 on CRYs, and their combined actions at different subcellular locations stabilize oscillation of the circadian clock.