期刊
BIOCHEMICAL JOURNAL
卷 475, 期 -, 页码 1507-1522出版社
PORTLAND PRESS LTD
DOI: 10.1042/BCJ20180005
关键词
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资金
- National Basic Research Program of China [973 Program] [2012CB947602]
- National Natural Science Foundation of China [31470772, 81703535]
- China Postdoctoral Science Foundation [2017M611895]
- Natural Science Foundation of Jiangsu Higher Education Institutions of China [17KJD180005]
- Jiangsu Postdoctoral Science Foundation [1701130C]
- Jiangsu Key Laboratory of Neuropsychiatric Diseases [BM2013003]
- Priority Academic Program Development (PAPD) of Jiangsu Higher Education Institutions
Living organisms on the earth maintain a roughly 24 h circadian rhythm, which is regulated by circadian clock genes and their protein products. Post-translational modifications of core clock proteins could affect the circadian behavior. Although ubiquitination of core clock proteins was studied extensively, the reverse process, deubiquitination, has only begun to unfold and the role of this regulation on circadian function is not completely understood. Here, we use affinity purification and mass spectrometry analysis to identify probable ubiquitin carboxyl-terminal hydrolase FAF-X (USP9X) as an interacting protein of the core clock protein aryl hydrocarbon receptor nuclear translocator-like protein 1 (ARNTL or BMAL1). Through biochemical experiments, we discover that USP9X reduces BMAL1 ubiquitination, enhances its stability, and increases its protein level, leading to the elevated transcriptional activity. Bioluminescence measurement reveals that USP9X knockdown decreases the amplitude of the cellular circadian rhythm but the period and phase are not affected. Our experiments find a new regulator for circadian clock at the post-translational level and demonstrate a different regulatory function for the circadian clock through the deubiquitination and the up-regulation of the core clock protein BMAL1 in the positive limb of the transcription-translation feedback loop.
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