The Histone Deacetylases Hst1 and Rpd3 Integrate De Novo NAD Metabolism with Phosphate Sensing in .

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 , we show that histone deacetylases (HDACs) Hst1 and Rpd3 link the regulation of the de novo NAD metabolism-mediating genes with certain aspects of the phosphate (Pi)-sensing 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 -activating Bas1-Pho2 complex and the -activating Pho2-Pho4 complex helps balance de novo activity with 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 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.