Regulation of a Cyclin-CDK-CDK Inhibitor Complex by Inositol Pyrophosphates

In budding yeast, phosphate starvation triggers inhibition of the Pho80-Pho85 cyclin–cyclin-dependent kinase (CDK) complex by the CDK inhibitor Pho81, leading to expression of genes involved in nutrient homeostasis. We isolated myo -d-inositol heptakisphosphate (IP 7 ) as a cellular component that stimulates Pho81-dependent inhibition of Pho80-Pho85. IP 7 is necessary for Pho81-dependent inhibition of Pho80-Pho85 in vitro. Moreover, intracellular concentrations of IP 7 increased upon phosphate starvation, and yeast mutants defective in IP 7 production failed to inhibit Pho80-Pho85 in response to phosphate starvation. These observations reveal regulation of a cyclin-CDK complex by a metabolite and suggest that a complex metabolic network mediates signaling of phosphate availability.