The Histone Deacetylases Hst1 and Rpd3 Integrate De Novo NAD⁺ Metabolism with Phosphate Sensing in Saccharomyces cerevisiae

Nicotinamide adenine dinucleotide (NAD⁺) is a critical cofactor essential for various cellular processes. Abnormalities in NAD⁺ metabolism have also been associated with a number of metabolic disorders. The regulation and interconnection of NAD⁺ metabolic pathways are not yet completely understood. By employing an NAD⁺ intermediate-specific genetic system established in the model organism S. cerevisiae, we show that histone deacetylases (HDACs) Hst1 and Rpd3 link the regulation of the de novo NAD⁺ metabolism-mediating BNA genes with certain aspects of the phosphate (Pi)-sensing PHO pathway. Our genetic and gene expression studies suggest that the Bas1-Pho2 and Pho2-Pho4 transcription activator complexes play a role in this co-regulation. Our results suggest a model in which competition for Pho2 usage between the BNA-activating Bas1-Pho2 complex and the PHO-activating Pho2-Pho4 complex helps balance de novo activity with PHO activity in response to NAD⁺ or phosphate depletion. Interestingly, both the Bas1-Pho2 and Pho2-Pho4 complexes appear to also regulate the expression of the salvage-mediating PNC1 gene negatively. These results suggest a mechanism for the inverse regulation between the NAD⁺ salvage pathways and the de novo pathway observed in our genetic models. Our findings help provide a molecular basis for the complex interplay of two different aspects of cellular metabolism.