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TORC1 signaling modulates Cdk8-dependent GAL gene expression in Saccharomyces cerevisiae

Riley Horvath1, Nicole Hawe1, Cindy Lam1

  • 1Department of Biochemistry and Molecular Biology, Molecular Epigenetics Group, LSI, University of British Columbia, Vancouver, BC V6T 1Z3, Canada.

Genetics
|December 1, 2021
PubMed

Insights

Nutrient signaling via TORC1 regulates gene expression by controlling Cdk8 kinase activity. This study reveals TORC1 signaling impacts Cdk8-dependent Gal4 phosphorylation through PP2A/Cdc55 phosphatase, modulating GAL gene induction.

Area of Science:

  • Molecular Biology
  • Gene Regulation
  • Signal Transduction

Background:

  • Cyclin-dependent kinase 8 (Cdk8) is a crucial component of the RNA polymerase II mediator complex, regulating gene expression through transcription factor phosphorylation.
  • The precise signals and mechanisms governing Cdk8 activity and substrate phosphorylation remain largely uncharacterized, particularly in the context of conserved eukaryotic pathways.
  • Full induction of yeast GAL genes necessitates Cdk8-mediated phosphorylation of the transcriptional activator Gal4.

Purpose of the Study:

  • To identify novel regulators of Cdk8-dependent Gal4 phosphorylation.
  • To elucidate the mechanisms by which nutrient signaling pathways influence Cdk8 activity and gene induction.
  • To investigate the interplay between TORC1 signaling, PP2A/Cdc55, and Cdk8 in regulating transcription.

Main Methods:

  • A genetic screen was employed to identify mutants affecting Cdk8-dependent Gal4 phosphorylation.
  • Analysis of TORC1 signaling pathway components, including rapamycin sensitivity and transcription factor localization.
  • In vitro kinase assays for Cdk8 activity and in vivo phosphorylation site analysis of Gal4.

Main Results:

  • Mutants with defects in TORC1 signaling, including a novel allele of hom3 (gft1), were identified.
  • hom3 and tor1 mutations impaired Gal4 phosphorylation at the Cdk8 site in vivo but did not affect Cdk8 kinase activity in vitro.
  • Disruption of cdc55, a PP2A regulatory subunit, rescued GAL gene expression and Gal4 phosphorylation defects caused by hom3 and tor1 mutations.

Conclusions:

  • TORC1 signaling pathway regulates GAL gene induction via the PP2A/Cdc55 phosphatase.
  • Cdk8-dependent Gal4 phosphorylation is antagonized by PP2A/Cdc55-mediated dephosphorylation.
  • Global nutritional signals, through TORC1, modulate Cdk8-dependent transcription initiation.
Keywords:
GAL genesCdc55Cdk8Gal4PP2ATorphosphorylationtranscriptionyeast

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