CRYPTOCHROMES promote daily protein homeostasis

EMBO J. 2022 Jan 4;41(1):e108883. doi: 10.15252/embj.2021108883. Epub 2021 Nov 29.


The daily organisation of most mammalian cellular functions is attributed to circadian regulation of clock-controlled protein expression, driven by daily cycles of CRYPTOCHROME-dependent transcriptional feedback repression. To test this, we used quantitative mass spectrometry to compare wild-type and CRY-deficient fibroblasts under constant conditions. In CRY-deficient cells, we found that temporal variation in protein, phosphopeptide, and K+ abundance was at least as great as wild-type controls. Most strikingly, the extent of temporal variation within either genotype was much smaller than overall differences in proteome composition between WT and CRY-deficient cells. This proteome imbalance in CRY-deficient cells and tissues was associated with increased susceptibility to proteotoxic stress, which impairs circadian robustness, and may contribute to the wide-ranging phenotypes of CRY-deficient mice. Rather than generating large-scale daily variation in proteome composition, we suggest it is plausible that the various transcriptional and post-translational functions of CRY proteins ultimately act to maintain protein and osmotic homeostasis against daily perturbation.

Keywords: CRYPTOCHROME; circadian rhythm; clock mutant; protein homeostasis; proteotoxic stress.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Circadian Rhythm / physiology*
  • Cryptochromes / deficiency
  • Cryptochromes / metabolism*
  • Ion Transport
  • Mice
  • Phosphoproteins / metabolism
  • Proteasome Endopeptidase Complex / metabolism
  • Proteome / metabolism
  • Proteomics
  • Proteostasis*
  • Reproducibility of Results
  • Stress, Physiological
  • Time Factors


  • Cryptochromes
  • Phosphoproteins
  • Proteome
  • Proteasome Endopeptidase Complex