Experimental and therapeutic medicineAug 9, 2020

The protein HRD1 affects the body’s internal clock by controlling the stability of BMAL1

Circadian Biology Weekly Brief ↗PubMed ↗DOI ↗

Updated Mar 27, 2026

Abstract

The E3 ubiquitin ligase HRD1 is associated with enhanced ubiquitination and degradation of BMAL1 protein.

HRD1 interacts with BMAL1, a key component of the circadian clock.
This interaction promotes K48-associated polyubiquitination of BMAL1.
HRD1-mediated degradation of BMAL1 is carried out through the ubiquitin-proteasome system.
The stability of BMAL1, regulated by HRD1, affects the expression of BMAL1 target genes.
Changes in BMAL1 stability may influence the amplitude of circadian oscillations in mammalian cells.

Simplified

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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The protein HRD1 affects the body’s internal clock by controlling the stability of BMAL1

Abstract

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