Department of Microbiology and Molecular Genetics, College of Biological Sciences, University of California, Davis, CA 95616, USA.
Int J Mol Sci. 2023 Apr 28;24(9):8047. doi: 10.3390/ijms24098047.
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.
烟酰胺腺嘌呤二核苷酸（NAD）是一种关键的辅酶，对于各种细胞过程至关重要。NAD 代谢异常也与许多代谢紊乱有关。NAD 代谢途径的调节和相互联系尚未完全理解。通过在模式生物中建立的 NAD 中间物特异性遗传系统，我们发现组蛋白脱乙酰酶（HDACs）Hst1 和 Rpd3 将新合成 NAD 代谢调节基因与某些磷酸（Pi）感应途径的方面联系起来。我们的遗传和基因表达研究表明，Bas1-Pho2 和 Pho2-Pho4 转录激活复合物在这种共调节中发挥作用。我们的结果提出了一个模型，即 Pho2 使用的竞争在激活 Bas1-Pho2 复合物和激活 Pho2-Pho4 复合物之间进行，有助于平衡新合成的活性和活性，以响应 NAD 或磷酸盐耗竭。有趣的是，Bas1-Pho2 和 Pho2-Pho4 复合物似乎也负调节挽救途径调节基因的表达。这些结果表明，在我们的遗传模型中观察到的 NAD 挽救途径和从头途径之间的反向调节的一种机制。我们的发现有助于为细胞代谢的两个不同方面的复杂相互作用提供分子基础。
