Cryptochromes-Mediated Inhibition of the CRL4 Cop1 -Complex Assembly Defines an Evolutionary Conserved Signaling Mechanism

In plants, Cryptochromes are photoreceptors that negatively regulate CRL4Cop1 (Cul4-RING ubiquitin ligase and its substrate receptor Cop1). 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 mouse liver. Mechanistically, Cryptochromes inactivate Cop1 by interacting with Det1, a specific subunit of the mammalian CRL4Cop1 complex. 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 cryptochrome-Cop1 axis originated.