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Curr Biol. 2019 Jun 17;29(12):1954-1962.e4. doi: 10.1016/j.cub.2019.04.073. Epub 2019 May 30.

Cryptochromes-Mediated Inhibition of the CRL4Cop1-Complex Assembly Defines an Evolutionary Conserved Signaling Mechanism.

Author information

1
Department of Biochemistry and Molecular Pharmacology, Perlmutter NYU Cancer Center, New York University School of Medicine, New York, NY 10016, USA; Howard Hughes Medical Institute, New York University School of Medicine, New York, NY 10016, USA. Electronic address: luca.rizzini@nyumc.org.
2
Division of Endocrinology, Metabolism and Molecular Medicine, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
3
Division of Endocrinology, Metabolism and Molecular Medicine, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA; Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
4
Department of Biochemistry and Molecular Pharmacology, Perlmutter NYU Cancer Center, New York University School of Medicine, New York, NY 10016, USA; Howard Hughes Medical Institute, New York University School of Medicine, New York, NY 10016, USA. Electronic address: michele.pagano@nyumc.org.

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.

KEYWORDS:

CRL4; Cop1; Cul4; Det1; c-Jun; circadian clock; cryptochromes; glucagon; glucocorticoid receptor; transrepression

PMID:
31155351
PMCID:
PMC6581574
[Available on 2020-06-17]
DOI:
10.1016/j.cub.2019.04.073

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