E3 ubiquitin ligase HRD1 modulates the circadian clock through regulation of BMAL1 stability

Guo,Dongkai; Zhu,Yao; Wang,Hongfeng; Wang,Guanghui; Wang,Cheng; Ren,Haigang

doi:10.3892/etm.2020.8988

E3 ubiquitin ligase HRD1 modulates the circadian clock through regulation of BMAL1 stability

Authors:
- Dongkai Guo
- Yao Zhu
- Hongfeng Wang
- Guanghui Wang
- Cheng Wang
- Haigang Ren
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Affiliations: Laboratory of Clinical Pharmacy, Department of Pharmacy, The Affiliated Suzhou Science and Technology Town Hospital of Nanjing Medical University, Suzhou, Jiangsu 215153, P.R. China, Laboratory of Molecular Neuropathology, Jiangsu Key Laboratory of Neuropsychiatric Disorders and Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu 215123, P.R. China
Published online on: July 10, 2020 https://doi.org/10.3892/etm.2020.8988
Pages: 2639-2648
Copyright: © Guo et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Circadian rhythm serves an essential role in numerous physiological functions. Circadian oscillations are organized by circadian clock components at the molecular level. The precision of the circadian clock is controlled by transcriptional‑translational negative feedback loops, as well as post‑translational modiﬁcations of clock proteins, including ubiquitination; however, the influence of E3 ligases on clock protein ubiquitination requires further investigation. The results of co‑immunoprecipitation and immunofluorescent localization, indicated that the endoplasmic reticulum transmembrane E3 ubiquitin ligase HRD1, encoded by the synoviolin 1 gene, interacted with brain and muscle ARNT‑like 1 (BMAL1) and enhanced BMAL1 protein ubiquitination. In addition, the results of western blotting and reverse transcription‑quantitative PCR suggested that HRD1 promoted K48‑associated polyubiquitination of BMAL1 and thus mediated its degradation via the ubiquitin‑proteasome system. Furthermore, gene knockdown and gene overexpression assays revealed that HRD1‑dependent degradation of BMAL1 protein regulated the expression of BMAL1 target genes and the amplitude of circadian oscillations in mammalian cells. The findings of the current study indicate that HRD1 may influence the regulation of circadian rhythm via modulation of BMAL1 stability.

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