Phosphorylation of N-terminal regions of REV-ERBs 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 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-ERB and REV-ERB 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-ERB 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.