Phosphorylation of N‐terminal regions of REV ‐ ERB s regulates their intracellular localization

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 ROR s and REV ‐ ERB s, respectively. Thus, the dynamics of the ROR s and REV ‐ ERB s 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 ‐ ERB α and REV ‐ ERB β determined both their own CK 1‐catalyzed phosphorylation and the cytoplasmic accumulation of each hyperphosphorylated form. Of the homologous N‐terminal regions, three serine‐rich clusters in REV ‐ ERB β are required for the phosphorylation and cytoplasmic localization. Our results indicate that the REV ‐ ERB s phosphorylation by CK 1 plays a key role in their subcellular localization, thereby controlling the timings of the transcriptional activation and inhibition of Bmal1 .