Ubiquitin ligase TRAF2 attenuates the transcriptional activity of the core clock protein BMAL1 and affects the maximal Per1 mRNA level of the circadian clock in cells
Ubiquitin ligase TRAF2 attenuates the transcriptional activity of the core clock protein BMAL1 and affects the maximal Per1 mRNA level of the circadian clock in cells
复制标题
泛素连接酶 TRAF2 减弱核心时钟蛋白 BMAL1 的转录活性并影响细胞中生物钟的最大 Per1 mRNA 水平
DOI：
10.1111/febs.14595
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发表时间：
2018-08-01
期刊：
影响因子：
5.4
通讯作者：
Xu, Guoqiang
中科院分区：
文献类型：
--
作者：
Chen, Suping;Yang, Jing;Xu, Guoqiang
泛素-蛋白酶体系统（UPS）调节许多蛋白质的泛素化和降解，从而改变它们的丰度和生物学功能。核心时钟蛋白，芳香烃受体核转位样蛋白1（ARNTL或BMAL 1），是生物钟的主要调节者，在许多生物过程的调节中起着重要作用，如蛋白质合成，细胞衰老和昼夜节律。然而，UPS对BMAL 1的影响尚未完全了解。在这里，我们发现E3泛素连接酶，TNF受体相关因子2（TRAF 2），作为BMAL 1的相互作用蛋白，以降低其稳定性。生化实验表明，这种调节是通过泛素化和随后的降解BMAL 1实现的。我们进一步揭示，BMAL 1优先与锌指结构域相互作用，而不是传统的底物识别结构域的TRAF 2。功能研究发现，TRAF 2表达降低了BMAL 1转录活性，而Traf 2敲低则提高了神经母细胞瘤细胞系中昼夜节律钟的最大Per 1 mRNA水平。这项工作发现TRAF 2作为一种新的调节因子BMAL 1，并揭示了一个新的结构域在TRAF 2的底物结合，这可能会扩展TRAF 2和BMAL 1在许多生物过程中的调节功能，如昼夜节律。
The ubiquitin-proteasome system (UPS) modulates the ubiquitination and degradation of many proteins and thus alters their abundance and biological functions. The core clock protein, aryl hydrocarbon receptor nuclear translocator-like protein 1 (ARNTL or BMAL1), is the master regulator of the circadian clock and plays important roles in the regulation of many biological processes, such as protein synthesis, cell senescence, and circadian rhythms. However, the influence of the UPS on BMAL1 is not fully understood. Here, we find an E3 ubiquitin ligase, TNF receptor-associated factor 2 (TRAF2), as an interacting protein of BMAL1 to reduce its stability. Biochemical experiments demonstrate that this regulation is achieved through the ubiquitination and subsequent degradation of BMAL1. We further reveal that BMAL1 preferentially interacts with the zinc finger domain but not the conventional substrate recognition domain in TRAF2. Functional studies find that TRAF2 expression reduces the BMAL1 transcriptional activity and Traf2 knockdown elevates the maximal Per1 mRNA level of the circadian clock in a neuroblastoma cell line. This work discovers TRAF2 as a novel regulatory factor for BMAL1 and reveals a new domain in TRAF2 for substrate binding, which may extend the regulatory functions of TRAF2 and BMAL1 in many biological processes, such as circadian rhythm.