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Circadian rhythms

Calibrating the clock

Nature Reviews Molecular Cell Biology volume 10, page 817 (2009)Cite this article

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“AMPK couples metabolic and circadian signals to calibrate the circadian clock by affecting the stability of the peripheral clock component CRY1.”

To calibrate the circadian clock, mammals rely on the oscillatory expression of genes encoding clock components, such as cryptochrome 1 (Cry1), and this expression depends on post-translational modifications. In preliminary studies the authors identified potential CRY1 phosphorylation sites and showed that phosphorylation of two amino acid residues (Ser71 and Ser280) destabilized this protein. Specifically, a phosphomimic mutation of one of these residues increased the affinity of CRY1 for the ubiquitin ligase FBXL3 (F-box and leucine-rich repeat protein 3), which ubiquitylates and therefore degrades CRY1. The two CRY1 residues correspond to AMPK phosphorylation target sites. To test whether AMPK phosphorylates these residues in CRY1, CRY1 was expressed in wild-type and Ampk−/− mouse embryonic fibroblasts, which were treated with an AMPK agonist that acts upstream of AMPK to phosphorylate it. CRY1 was phosphorylated only in wild-type cells, indicating that AMPK carries out this process in vivo. Phosphorylated CRY1 from wild-type cells was less stable than CRY1 from Ampk−/− cells, suggesting that AMPK-mediated phosphorylation leads to CRY1 degradation.

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References

ORIGINAL RESEARCH PAPER

  1. Lamia, K. A. et al. AMPK regulates the circadian clock by cryptochrome phosphorylation and degradation. Science 326, 437–440 (2009)

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FURTHER READING

  1. Gallego, M. & Virshup, D. M. Post-translational modifications regulate the ticking of the circadian clock. Nature Rev. Mol. Cell Biol. 8, 139–148 (2007)

    Article  CAS  Google Scholar 

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Authors
  1. Rachel David
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David, R. Calibrating the clock. Nat Rev Mol Cell Biol 10, 817 (2009). https://doi.org/10.1038/nrm2806

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