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.

Automated summary

The histone deacetylases Hst1 and Rpd3 are shown to link the regulation of the BNA genes involved in de novo NAD(+) metabolism with the PHO pathway through the Bas1-Pho2 and Pho2-Pho4 transcription activator complexes. The study provides insights into the complex interplay between two different aspects of cellular metabolism.