Phosphorylation of N‐terminal regions of REV‐ERBs regulates their intracellular localization

Mar 7, 2018Genes to cells : devoted to molecular & cellular mechanisms

Phosphorylation of REV-ERB proteins' front regions controls their location inside cells

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Abstract

Phosphorylation by CK1 is crucial for the subcellular localization of REV-ERBs, influencing Bmal1 transcription.

Circadian rhythms in mammals rely on the expression of clock genes regulated by feedback loops.
Bmal1, a key clock gene, shows a nocturnal transcriptional pattern in the mouse brain's suprachiasmatic nucleus.
RORs induce and REV-ERBs repress the transcription of Bmal1.
REV-ERBα and REV-ERBβ share highly homologous N-terminal regions that affect their phosphorylation and localization.
Three serine-rich clusters in the N-terminal region of REV-ERBβ are necessary for its phosphorylation and cytoplasmic localization.
REV-ERB phosphorylation by CK1 is associated with the timing of Bmal1 transcriptional regulation.

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Circadian rhythms are generated by the cyclic expression of several clock genes in mammals. The rhythmic expression of these genes is maintained by multiple transcriptional-translational feedback loops in addition to the posttranslational regulation of the clock proteins. Transcription of one of the key clock genes, Bmal1, which exhibits a nocturnal transcriptional rhythm in the suprachiasmatic nucleus of the mouse brain, is induced and repressed by RORs and REV-ERBs, respectively. Thus, the dynamics of the RORs and REV-ERBs expression, modification, subcellular localization and degradation of these transcriptional factors are critical for the transcriptional regulation of Bmal1. In this study, we found that the highly homologous N-terminal regions of REV-ERBα and REV-ERBβ determined both their own CK1-catalyzed phosphorylation and the cytoplasmic accumulation of each hyperphosphorylated form. Of the homologous N-terminal regions, three serine-rich clusters in REV-ERBβ are required for the phosphorylation and cytoplasmic localization. Our results indicate that the REV-ERBs phosphorylation by CK1 plays a key role in their subcellular localization, thereby controlling the timings of the transcriptional activation and inhibition of Bmal1.

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Phosphorylation of N‐terminal regions of REV‐ERBs regulates their intracellular localization

Abstract

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