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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

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.