CDK8-cyclin C mediates nutritional regulation of developmental transitions through the ecdysone receptor in Drosophila

Xiao Jun Xie, Fu Ning Hsu, Xinsheng Gao, Wu Xu, Jian Quan Ni, Yue Xing, Liying Huang, Hao Ching Hsiao, Haiyan Zheng, Chenguang Wang, Yani Zheng, Alus Michael Xiaoli, Fajun Yang, Sarah E. Bondos, Jun Yuan Ji

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Abstract

The steroid hormone ecdysone and its receptor (EcR) play critical roles in orchestrating developmental transitions in arthropods. However, the mechanism by which EcR integrates nutritional and developmental cues to correctly activate transcription remains poorly understood. Here, we show that EcR-dependent transcription, and thus, developmental timing in Drosophila, is regulated by CDK8 and its regulatory partner Cyclin C (CycC), and the level of CDK8 is affected by nutrient availability. We observed that cdk8 and cycC mutants resemble EcR mutants and EcR-target genes are systematically down-regulated in both mutants. Indeed, the ability of the EcR-Ultraspiracle (USP) heterodimer to bind to polytene chromosomes and the promoters of EcR target genes is also diminished. Mass spectrometry analysis of proteins that co-immunoprecipitate with EcR and USP identified multiple Mediator subunits, including CDK8 and CycC. Consistently, CDK8-CycC interacts with EcR-USP in vivo; in particular, CDK8 and Med14 can directly interact with the AF1 domain of EcR. These results suggest that CDK8-CycC may serve as transcriptional cofactors for EcR-dependent transcription. During the larval–pupal transition, the levels of CDK8 protein positively correlate with EcR and USP levels, but inversely correlate with the activity of sterol regulatory element binding protein (SREBP), the master regulator of intracellular lipid homeostasis. Likewise, starvation of early third instar larvae precociously increases the levels of CDK8, EcR and USP, yet down-regulates SREBP activity. Conversely, refeeding the starved larvae strongly reduces CDK8 levels but increases SREBP activity. Importantly, these changes correlate with the timing for the larval–pupal transition. Taken together, these results suggest that CDK8-CycC links nutrient intake to developmental transitions (EcR activity) and fat metabolism (SREBP activity) during the larval–pupal transition.

Original languageEnglish (US)
JournalPLoS Biology
Volume13
Issue number7
DOIs
StatePublished - 2015

Fingerprint

Cyclin C
ecdysone
cyclins
Drosophila
receptors
Sterol Regulatory Element Binding Proteins
sterols
binding proteins
Transcription
transcription (genetics)
ecdysone receptor
mutants
Nutrients
Larva
Genes
Steroid hormones
Polytene Chromosomes
Food
polytene chromosomes
Aptitude

ASJC Scopus subject areas

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

Cite this

CDK8-cyclin C mediates nutritional regulation of developmental transitions through the ecdysone receptor in Drosophila. / Xie, Xiao Jun; Hsu, Fu Ning; Gao, Xinsheng; Xu, Wu; Ni, Jian Quan; Xing, Yue; Huang, Liying; Hsiao, Hao Ching; Zheng, Haiyan; Wang, Chenguang; Zheng, Yani; Xiaoli, Alus Michael; Yang, Fajun; Bondos, Sarah E.; Ji, Jun Yuan.

In: PLoS Biology, Vol. 13, No. 7, 2015.

Research output: Contribution to journalArticle

Xie, XJ, Hsu, FN, Gao, X, Xu, W, Ni, JQ, Xing, Y, Huang, L, Hsiao, HC, Zheng, H, Wang, C, Zheng, Y, Xiaoli, AM, Yang, F, Bondos, SE & Ji, JY 2015, 'CDK8-cyclin C mediates nutritional regulation of developmental transitions through the ecdysone receptor in Drosophila', PLoS Biology, vol. 13, no. 7. https://doi.org/10.1371/journal.pbio.1002207
Xie, Xiao Jun ; Hsu, Fu Ning ; Gao, Xinsheng ; Xu, Wu ; Ni, Jian Quan ; Xing, Yue ; Huang, Liying ; Hsiao, Hao Ching ; Zheng, Haiyan ; Wang, Chenguang ; Zheng, Yani ; Xiaoli, Alus Michael ; Yang, Fajun ; Bondos, Sarah E. ; Ji, Jun Yuan. / CDK8-cyclin C mediates nutritional regulation of developmental transitions through the ecdysone receptor in Drosophila. In: PLoS Biology. 2015 ; Vol. 13, No. 7.
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abstract = "The steroid hormone ecdysone and its receptor (EcR) play critical roles in orchestrating developmental transitions in arthropods. However, the mechanism by which EcR integrates nutritional and developmental cues to correctly activate transcription remains poorly understood. Here, we show that EcR-dependent transcription, and thus, developmental timing in Drosophila, is regulated by CDK8 and its regulatory partner Cyclin C (CycC), and the level of CDK8 is affected by nutrient availability. We observed that cdk8 and cycC mutants resemble EcR mutants and EcR-target genes are systematically down-regulated in both mutants. Indeed, the ability of the EcR-Ultraspiracle (USP) heterodimer to bind to polytene chromosomes and the promoters of EcR target genes is also diminished. Mass spectrometry analysis of proteins that co-immunoprecipitate with EcR and USP identified multiple Mediator subunits, including CDK8 and CycC. Consistently, CDK8-CycC interacts with EcR-USP in vivo; in particular, CDK8 and Med14 can directly interact with the AF1 domain of EcR. These results suggest that CDK8-CycC may serve as transcriptional cofactors for EcR-dependent transcription. During the larval–pupal transition, the levels of CDK8 protein positively correlate with EcR and USP levels, but inversely correlate with the activity of sterol regulatory element binding protein (SREBP), the master regulator of intracellular lipid homeostasis. Likewise, starvation of early third instar larvae precociously increases the levels of CDK8, EcR and USP, yet down-regulates SREBP activity. Conversely, refeeding the starved larvae strongly reduces CDK8 levels but increases SREBP activity. Importantly, these changes correlate with the timing for the larval–pupal transition. Taken together, these results suggest that CDK8-CycC links nutrient intake to developmental transitions (EcR activity) and fat metabolism (SREBP activity) during the larval–pupal transition.",
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AU - Ni, Jian Quan

AU - Xing, Yue

AU - Huang, Liying

AU - Hsiao, Hao Ching

AU - Zheng, Haiyan

AU - Wang, Chenguang

AU - Zheng, Yani

AU - Xiaoli, Alus Michael

AU - Yang, Fajun

AU - Bondos, Sarah E.

AU - Ji, Jun Yuan

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