The time-dependent degradation of core circadian clock proteins is essential for the proper functioning of circadian timekeeping mechanisms that drive daily rhythms in gene expression and, ultimately, an organism's physiology. The ubiquitin proteasome system plays a critical role in regulating the stability of most proteins, including the core clock components. Our laboratory developed a cell-based functional screen to identify ubiquitin ligases that degrade any protein of interest and have started screening for those ligases that degrade circadian clock proteins. This screen identified Spsb4 as a putative novel E3 ligase for RevErbα. In this article, we further investigate the role of Spsb4 and its paralogs in RevErbα stability and circadian rhythmicity. Our results indicate that the paralogs Spsb1 and Spsb4, but not Spsb2 and Spsb3, can interact with and facilitate RevErbα ubiquitination and degradation and regulate circadian clock periodicity.

中文翻译：

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E3 Ligases Spsb1和Spsb4调节RevErbα的降解和昼夜节律。

昼夜节律性时钟蛋白的时间依赖性降解对于昼夜节律机制的正常运行至关重要，这种机制会驱动基因表达中的日常节律，并最终影响生物的生理。泛素蛋白酶体系统在调节大多数蛋白质（包括核心时钟成分）的稳定性中起关键作用。我们的实验室开发了一种基于细胞的功能筛选器，以鉴定可降解任何目标蛋白的泛素连接酶，并已开始筛选可降解昼夜节律蛋白的连接酶。该屏幕将Spsb4鉴定为RevErbα的新型E3连接酶。在本文中，我们将进一步研究Spsb4及其旁系同源物在RevErbα稳定性和昼夜节律方面的作用。我们的结果表明，旁系同源词Spsb1和Spsb4，而不是Spsb2和Spsb3，