CRYPTOCHROMES promote daily protein homeostasis.


Change log
Abstract

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.

Publication Date
2022-01-04
Online Publication Date
2021-11-29
Acceptance Date
2021-11-09
Keywords
CRYPTOCHROME, circadian rhythm, clock mutant, protein homeostasis, proteotoxic stress, Animals, Circadian Rhythm, Cryptochromes, Ion Transport, Mice, Phosphoproteins, Proteasome Endopeptidase Complex, Proteome, Proteomics, Proteostasis, Reproducibility of Results, Stress, Physiological, Time Factors
Journal Title
EMBO J
Journal ISSN
0261-4189
1460-2075
Volume Title
Publisher
EMBO
Sponsorship
Wellcome Trust (093734/Z/10/Z)