PMID- 29935055 OWN - NLM STAT- MEDLINE DCOM- 20190614 LR - 20190614 IS - 1742-4658 (Electronic) IS - 1742-464X (Linking) VI - 285 IP - 16 DP - 2018 Aug TI - 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. PG - 2987-3001 LID - 10.1111/febs.14595 [doi] AB - 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. CI - (c) 2018 Federation of European Biochemical Societies. FAU - Chen, Suping AU - Chen S AD - Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Soochow University, Suzhou, Jiangsu, China. FAU - Yang, Jing AU - Yang J AD - Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Soochow University, Suzhou, Jiangsu, China. FAU - Yang, Lu AU - Yang L AD - Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Soochow University, Suzhou, Jiangsu, China. FAU - Zhang, Yang AU - Zhang Y AD - Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Soochow University, Suzhou, Jiangsu, China. FAU - Zhou, Liang AU - Zhou L AD - Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Soochow University, Suzhou, Jiangsu, China. FAU - Liu, Qing AU - Liu Q AD - Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Soochow University, Suzhou, Jiangsu, China. FAU - Duan, Chunyan AU - Duan C AD - Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Soochow University, Suzhou, Jiangsu, China. FAU - Mieres, Crystal A AU - Mieres CA AD - Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Soochow University, Suzhou, Jiangsu, China. AD - Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin, Ireland. FAU - Zhou, Guanghai AU - Zhou G AD - Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Soochow University, Suzhou, Jiangsu, China. AD - Institute of Cardiovascular Endocrinology, Key Laboratory of Atherosclerosis in Universities of Shandong, Taishan Medical University, Tai'an, Shandong, China. FAU - Xu, Guoqiang AU - Xu G AD - Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Soochow University, Suzhou, Jiangsu, China. LA - eng GR - 31470772/National Natural Science Foundation of China/International GR - 81703535/National Natural Science Foundation of China/International GR - 973 Program/National Basic Research Program of China/International GR - 2012CB947602/National Basic Research Program of China/International GR - 2017M611895/China Postdoctoral Science Foundation/International GR - 17KJD180005/Natural Science Foundation of Jiangsu Higher Education Institutions of China/International GR - 1701130C/Jiangsu Postdoctoral Science Foundation/International GR - BM2013003/Jiangsu Key Laboratory of Neuropsychiatric Diseases/International GR - Priority Academic Program Development (PAPD) of Jiangsu Higher Education Institutions/International GR - SU-RCSI International Research Summer School Program/International GR - Visiting Scholarship for Young Faculty of Shangdong Higher Education Institutions/International PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20180705 PL - England TA - FEBS J JT - The FEBS journal JID - 101229646 RN - 0 (ARNTL Transcription Factors) RN - 0 (CRY1 protein, human) RN - 0 (Cryptochromes) RN - 0 (PSMD2 protein, human) RN - 0 (Per1 protein, mouse) RN - 0 (Period Circadian Proteins) RN - 0 (RNA, Messenger) RN - 0 (TNF Receptor-Associated Factor 2) RN - 0 (TRAF2 protein, mouse) RN - EC 2.3.2.27 (Ubiquitin-Protein Ligases) SB - IM MH - ARNTL Transcription Factors/genetics/*metabolism MH - Animals MH - Circadian Clocks/*genetics MH - Cryptochromes/genetics/metabolism MH - HEK293 Cells MH - Humans MH - Mice MH - Period Circadian Proteins/*genetics/metabolism MH - Protein Interaction Domains and Motifs MH - Protein Interaction Mapping MH - Protein Stability MH - RNA, Messenger MH - TNF Receptor-Associated Factor 2/genetics/*metabolism MH - Ubiquitin-Protein Ligases/metabolism MH - Ubiquitination MH - Zinc Fingers OTO - NOTNLM OT - BMAL1 OT - TRAF2 OT - circadian clock OT - degradation OT - ubiquitination EDAT- 2018/06/24 06:00 MHDA- 2019/06/15 06:00 CRDT- 2018/06/24 06:00 PHST- 2017/12/25 00:00 [received] PHST- 2018/05/30 00:00 [revised] PHST- 2018/06/21 00:00 [accepted] PHST- 2018/06/24 06:00 [pubmed] PHST- 2019/06/15 06:00 [medline] PHST- 2018/06/24 06:00 [entrez] AID - 10.1111/febs.14595 [doi] PST - ppublish SO - FEBS J. 2018 Aug;285(16):2987-3001. doi: 10.1111/febs.14595. Epub 2018 Jul 5.