Cryptochromes-mediated Inhibition of the CRL4Cop1-Complex Assembly Defines an Evolutionary Conserved signaling mechanism
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE124388 | GEO | 2019/05/01
REPOSITORIES: GEO
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Project description: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.
| S-EPMC6581574 | biostudies-literature
Project description:Cryptochromes-mediated Inhibition of the CRL4Cop1-Complex Assembly Defines an Evolutionary Conserved signaling mechanism
| PRJNA511889 | ENA
Project description:The circadian transcriptional repressors cryptochromes 1 (Cry1) and 2 (Cry2) interact with the C-terminus of the glucocorticoid receptor (GR) and are required for transrepression in response to the synthetic GR ligand dexamethasone (Dex) in mouse embryonic fibroblasts. Dex induction of many genes was increased in Cry-deficient fibroblasts suggesting that cryptochromes oppose transactivation in addition to contributing to transrepression. In mice, genetic loss of Cry1 and/or Cry2 resulted in glucose intolerance and constitutively high levels of circulating corticosterone, suggesting reduced glucocorticoid suppression of the hypothalamic-pituitary-adrenal axis coupled with increased sensitivity to the hyperglycemic effects of glucocorticoid-mediated transactivation in the liver. Cry1 and Cry2 association with a GRE in the Pck1 promoter was stimulated by Dex, and Dex-induced transcription of pck1 was strikingly increased in Cry-deficient livers. Finally, cry1-/-;cry2-/- mice subjected to 8 weeks of chronic Dex treatment exhibited incomplete suppression of circulating corticosterone and greater glucose intolerance compared with wildtype littermates subjected to the same chronic treatment, consistent with enhanced transcriptional response to the synthetic glucocorticoid ligand. Total RNA was obtained from WT and Cry1/2 KO MEFs treated with Dexamethasone (1uM) or control EtOH for 16 hours.
2011-12-22 | E-GEOD-24469 | biostudies-arrayexpress
Project description:The circadian transcriptional repressors cryptochromes 1 (Cry1) and 2 (Cry2) interact with the C-terminus of the glucocorticoid receptor (GR) and are required for transrepression in response to the synthetic GR ligand dexamethasone (Dex) in mouse embryonic fibroblasts. Dex induction of many genes was increased in Cry-deficient fibroblasts suggesting that cryptochromes oppose transactivation in addition to contributing to transrepression. In mice, genetic loss of Cry1 and/or Cry2 resulted in glucose intolerance and constitutively high levels of circulating corticosterone, suggesting reduced glucocorticoid suppression of the hypothalamic-pituitary-adrenal axis coupled with increased sensitivity to the hyperglycemic effects of glucocorticoid-mediated transactivation in the liver. Cry1 and Cry2 association with a GRE in the Pck1 promoter was stimulated by Dex, and Dex-induced transcription of pck1 was strikingly increased in Cry-deficient livers. Finally, cry1-/-;cry2-/- mice subjected to 8 weeks of chronic Dex treatment exhibited incomplete suppression of circulating corticosterone and greater glucose intolerance compared with wildtype littermates subjected to the same chronic treatment, consistent with enhanced transcriptional response to the synthetic glucocorticoid ligand.
2011-12-22 | GSE24469 | GEO
Project description:Mammalian circadian clocks are driven by a transcription/translation feedback loop composed of positive regulators (CLOCK/BMAL1) and repressors (CRYPTOCHROME 1/2 (CRY1/2) and PER1/2). To understand the structural principles of regulation, we used evolutionary sequence analysis to identify co-evolving residues within the CRY/PHL protein family. Here we report the identification of an ancestral secondary cofactor-binding pocket as an interface in repressive CRYs, mediating regulation through direct interaction with CLOCK and BMAL1. Mutations weakening binding between CLOCK/BMAL1 and CRY1 lead to acceleration of the clock, suggesting that subtle sequence divergences at this site can modulate clock function. Divergence between CRY1 and CRY2 at this site results in distinct periodic output. Weaker interactions between CRY2 and CLOCK/BMAL1 at this pocket are strengthened by co-expression of PER2, suggesting that PER expression limits the length of the repressive phase in CRY2-driven rhythms. Overall, this work provides a model for the mechanism and evolutionary variation of clock regulatory mechanisms.
| S-EPMC5859286 | biostudies-literature
Project description:Cryptochromes are blue-light receptors in plants and animals. Homodimers are the physiologically active form of plant cryptochromes that mediates blue light regulation of gene expression and photomorphogenesis, but how light regulates the photoreceptor activation and inactivation remains unclear. We identified an Arabidopsis protein BIC1 (Blue-light Inhibitor of Cryptochromes 1) that inhibits all photoreactions of plant cryptochrome 2 (CRY2) examined, allowing direct tests of the photoactivation and inactivation mechanisms of CRY2. We found that blue light stimulates homodimerization of CRY2, whereas BIC1 binds to CRY2 to suppress CRY2 dimerization and the interaction of CRY2 with its signaling partners. We further show that cryptochromes and phytochromes mediate light induction of BIC1 transcription, evoking the negative feedback circuitry to control homeostasis of the active cryptochromes under the broad spectra of solar radiation in nature.
2016-12-02 | GSE80350 | GEO
Project description:Light is a crucial exogenous signal sensed by cryptochrome (CRY) blue light receptors to modulate growth and the circadian clock in plants and animals. However, how CRYs interpret light quantity to regulate growth in plants remains poorly understood. Furthermore, CRY2 protein levels and activity are tightly regulated in light to fine-tune hypocotyl growth; however, details of the mechanisms that explain precise control of CRY2 levels are not fully understood. We show that in Arabidopsis, UBP12 and UBP13 deubiquitinases physically interact with CRY2 in light. UBP12/13 negatively regulates CRY2 by promoting its ubiquitination and turnover to modulate hypocotyl growth. Growth and development were explicitly affected in blue light when UBP12/13 were disrupted or overexpressed, indicating their role alongside CRY2. UBP12/13 also interacted with and stabilized COP1, which is partially required for CRY2 turnover. Our combined genetic and molecular data support a mechanistic model in which UBP12/13 interact with CRY2 and COP1, leading to the stabilization of COP1. Stabilized COP1 then promotes the ubiquitination and degradation of CRY2 under blue light. Despite decades of studies on deubiquitinases, the knowledge of how their activity is regulated is limited. Our study provides insight into how exogenous signals and ligands, along with their receptors, regulate deubiquitinase activity by protein-protein interaction. Collectively, our results provide a framework of cryptochromes and deubiquitinases to detect and interpret light signals to control plant growth at the most appropriate time.
2022-06-13 | GSE201685 | GEO
Project description:Cryptochromes were identified in plants and animals where they function as either photoreceptors or circadian clock components. In the filamentous fungus Neurospora, the biological function of cryptochrome has not yet been explored. Here, we demonstrate that Neurospora crassa cryptochrome (Nc cry) is a DASH-type of cryptochrome, capable of binding FAD and MTHF, whose transcript and protein levels are both strongly induced by blue light in a wc-1 dependent manner. Although the Nc cry transcript is circadian-regulated and antiphasic to frq, knockout strains of Nc cry appears to have a normal clock phenotype. Whole genome microarray and RT-QPCR analysis confirm that Nc cry is not involved in the signal transduction of either early or late light responses and seems to have no transcriptional regulatory activity under our laboratory conditions. Our study concludes that the only cryptochrome in Neurospora crassa is dispensable for the well-characterized blue light sensing cascade and is not part of the circadian clock system. Keywords: light response
2010-03-31 | GSE14909 | GEO
Project description:Cryptochromes were identified in plants and animals where they function as either photoreceptors or circadian clock components. In the filamentous fungus Neurospora, the biological function of cryptochrome has not yet been explored. Here, we demonstrate that Neurospora crassa cryptochrome (Nc cry) is a DASH-type of cryptochrome, capable of binding FAD and MTHF, whose transcript and protein levels are both strongly induced by blue light in a wc-1 dependent manner. Although the Nc cry transcript is circadian-regulated and antiphasic to frq, knockout strains of Nc cry appears to have a normal clock phenotype. Whole genome microarray and RT-QPCR analysis confirm that Nc cry is not involved in the signal transduction of either early or late light responses and seems to have no transcriptional regulatory activity under our laboratory conditions. Our study concludes that the only cryptochrome in Neurospora crassa is dispensable for the well-characterized blue light sensing cascade and is not part of the circadian clock system. Keywords: light response Two-color microarray. Alexa Fluor 555 was consistently used to label cDNA synthesized from reference RNA, which is a mixture containing equal amounts of RNA samples harvested from different circadian time points and light treatment durations. The same batch of pooled RNA was used as a reference for each array experiment. Alexa Fluor 647 was used exclusively to label cDNA representing sample RNA.
2010-06-05 | E-GEOD-14909 | biostudies-arrayexpress
Project description:This RNA-seq data set investigates the function of the DASH cryptochrome CryD in the fungus Fusarium fujikuroi, and are an extension of the former study on the role of the WcoA photoreceptor (GEO Series GSE159533) (Pardo-Medina J, Gutiérrez G, Limón MC, Avalos J (2021) Impact of the White Collar photoreceptor WcoA on the Fusarium fujikuroi transcriptome. Front Microbiol 11:1–17. https://doi.org/10.3389/fmicb.2020.619474)). Cryptochromes are blue/UV-A light photoreceptors related to photolyases, enzymes able to use light as an energy source to repair UV-B-induced lesions. Cryptochromes typically have a N-terminal photolyase-related domain able to bind two chromophores, flavin adenine dinucleotide (FAD) and 5,10-methenyltetrahydrofolate (MTHF) or pterin, followed by a long C-terminal domain absent in photolyases, reported to play regulatory roles related to light control of growth, development, cell signaling, and circadian rhythm in different taxonomic groups. The DASH cryptochromes are a subgroup in this family that differ from cryptochromes in the ability to repair single-stranded DNA and the lack of the long carboxy extension. The Fusarium fujikuroi genome contains a single gene for a DASH cryptochrome, called CryD. In our former work, the function of the WcoA photoreceptor was investigated through the effect of the mutation of the responsible gene on the transcriptome . In this work, RNA samples of a cryD mutant were analyzed in parallel to those of the wild type and wcoA mutant described in GEO Series GSE159533, in dark and after one hour illumination. The results are summarized in the review "Fusarium photoreceptors", submitted for publication to Journal of Fungi (Basel, MDPI)
2023-04-04 | GSE223375 | GEO