Abstract
In plants, cryptochromes are photoreceptors that negatively regulate the ubiquitin ligase CRL4Cop1. In mammals, cryptochromes are core components of the circadian clock and repressors of the glucocorticoid receptor (GR). Moreover, mammalian cryptochromes lost their ability to interact with Cop1, suggesting that they are unable to inhibit CRL4Cop1. Contrary to this assumption, we found that mammalian cryptochromes are also negative regulators of CRL4Cop1, and through this mechanism, they repress the GR transcriptional network both in cultured cells and in the mouse liver. Mechanistically, cryptochromes inactivate Cop1 by interacting with Det1, a subunit of the mammalian CRL4Cop1 complex that is not present in other CRL4s. Through this interaction, the ability of Cop1 to join the CRL4 complex is inhibited; therefore, its substrates accumulate. Thus, the interaction between cryptochromes and Det1 in mammals mirrors the interaction between cryptochromes and Cop1 in planta, pointing to a common ancestor in which the cryptochromes-Cop1 axis originated. Rizzini et al. find that the cryptochromes-Cop1 axis is conserved in mammals. Cryptochromes inhibit CRL4Cop1 complex formation by competing with Cop1 to bind Det1. Through this molecular mechanism, the substrates of the CRL4Cop1 complex are stabilized, leading, among other effects, to repression of glucocorticoid receptor transcriptional activity.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1954-1962.e4 |
| Journal | Current Biology |
| Volume | 29 |
| Issue number | 12 |
| DOIs | |
| State | Published - Jun 17 2019 |
Funding
The authors thank the NYU Genome Technology Center (partially supported by the Cancer Center Support Grant P30CA016087 at the Laura and Isaac Perlmutter Cancer Center) for expert library preparation and sequencing for RNA sequencing (RNA-seq) and C. Lee and M. Karin for reagents. The mass spectrometric experiments were supported in part by NYU School of Medicine, the Laura and Isaac Perlmutter Cancer Center Support grant P30CA016087 from the National Cancer Institute, and a shared instrumentation grant from the NIH (1S10OD010582-01A1), for the purchase of an Orbitrap Fusion Lumos. M. Pagano is an Investigator with the Howard Hughes Medical Institute. M. Pagano is grateful to T.M. Thor for continuous support. This work was funded by grants from the NIH (R01-GM057587 and R01-CA076584 to M. Pagano, R01DK100814 and 2R01DK090625-05 to J.B. K01DK105137 to C.B.P. and F32HL143978 to M. Perelis). Conceptualization, Investigation, Methodology, Validation, Formal Analysis, Data Curation, Visualization, Project Administration, Writing – Original Draft, and Writing – Review and Editing, L.R.; Investigation (Mice Experimentation), Methodology, Resources, and Writing – Review and Editing, D.C.L. C.B.P. and J.B.; Software (Motif-Enrichment Analysis) and Writing – Review and Editing, M. Perelis; Supervision, Project Administration, Funding Acquisition, Resources, and Writing – Review and Editing, M. Pagano. M. Pagano is a consultant for BeyondSpring Pharmaceuticals and a member of the scientific advisory boards of CullGen and Kymera Therapeutics. The authors thank the NYU Genome Technology Center (partially supported by the Cancer Center Support Grant P30CA016087 at the Laura and Isaac Perlmutter Cancer Center ) for expert library preparation and sequencing for RNA sequencing (RNA-seq) and C. Lee and M. Karin for reagents. The mass spectrometric experiments were supported in part by NYU School of Medicine , the Laura and Isaac Perlmutter Cancer Center Support grant P30CA016087 from the National Cancer Institute , and a shared instrumentation grant from the NIH ( 1S10OD010582-01A1 ), for the purchase of an Orbitrap Fusion Lumos. M. Pagano is an Investigator with the Howard Hughes Medical Institute. M. Pagano is grateful to T.M. Thor for continuous support. This work was funded by grants from the NIH ( R01-GM057587 and R01-CA076584 to M. Pagano, R01DK100814 and 2R01DK090625-05 to J.B., K01DK105137 to C.B.P., and F32HL143978 to M. Perelis).
Keywords
- CRL4
- Cop1
- Cul4
- Det1
- c-Jun
- circadian clock
- cryptochromes
- glucagon
- glucocorticoid receptor
- transrepression
ASJC Scopus subject areas
- General Biochemistry, Genetics and Molecular Biology
- General Agricultural and Biological Sciences