Fig. 2

Scheme representing the same mammalian cell, e.g. SCN cell, showing the molecular circadian clock sequence of events that under normal entrainment conditions in nature, lasts 24 h. ① CLOCK and BMAL1 proteins form a heterodimer which activates the transcription of genes encoding other core components of the loop: e.g. Cryptochrome (Cry1 and Cry2), Period (Per1 and Per2), Nr1d1 (REV-ERB-α protein) or Ror-α. CLOCK and BMAL1 also regulate the transcription of the so-called clock controlled genes. Among these genes there are key factors in processes intimately related to immune response.② Cry and Per mRNAs are translated into CRY and PER proteins with levels increasing during the night and form a heterodimer. ③CK1δ and CK1ε phosphorilate CRY and PER proteins allowing their translocation into the nucleus. ④ In the nucleus, the CRY/PER heterodimer represses the BMAL1/CLOCK activity thereby inhibiting their own transcription. ⑤ CRY and PER proteins are ubiquinated leading to their degradation via the 26S proteosome. ⑥ CRY and PER levels decrease and with it their repression over BMAL1/CLOCK, allowing for a new cycle to start again and the completion of the 24-h feedback loop. BMAL1/CLOCK also regulate the expression of the nuclear receptors Nr1d1 (⑦ REV-ERB-α protein) and Ror-α (⑧ ROR-α protein) which will, in turn, repress or activate Bmal1 transcription