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

Luca Rizzini*, Daniel C. Levine, Mark Perelis, Joseph Bass, Clara B. Peek, Michele Pagano

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

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 languageEnglish (US)
Pages (from-to)1954-1962.e4
JournalCurrent Biology
Volume29
Issue number12
DOIs
StatePublished - Jun 17 2019

Keywords

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

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

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