The copper-sensing transcription factor Mac1, the histone deacetylase Hst1, and nicotinic acid regulate de novo NAD+ biosynthesis in budding yeast.

Christol James Theoga Raj, Trevor Croft, Padmaja Venkatakrishnan, Benjamin Groth, Gagandeep Dhugga, Timothy Cater, Su-Ju Lin

The Journal of biological chemistry 2019 Apr 05

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NADH (NAD+) is an essential metabolite involved in various cellular biochemical processes. The regulation of NAD+ metabolism is incompletely understood. Here, using budding yeast (Saccharomyces cerevisiae), we established an NAD+ intermediate-specific genetic system to identify factors that regulate the de novo branch of NAD+ biosynthesis. We found that a mutant strain (mac1Δ) lacking Mac1, a copper-sensing transcription factor that activates copper transport genes during copper deprivation, exhibits increases in quinolinic acid (QA) production and NAD+ levels. Similar phenotypes were also observed in the hst1Δ strain, deficient in the NAD+-dependent histone deacetylase Hst1, which inhibits de novo NAD+ synthesis by repressing BNA gene expression when NAD+ is abundant. Interestingly, the mac1Δ and hst1Δ mutants shared a similar NAD+ metabolism-related gene expression profile, and deleting either MAC1 or HST1 de-repressed the BNA genes. ChIP experiments with the BNA2 promoter indicated that Mac1 works with Hst1-containing repressor complexes to silence BNA expression. The connection of Mac1 and BNA expression suggested that copper stress affects de novo NAD+ synthesis, and we show that copper stress induces both BNA expression and QA production. Moreover, nicotinic acid inhibited de novo NAD+ synthesis through Hst1-mediated BNA repression, hindered the reuptake of extracellular QA, and thereby reduced de novo NAD+ synthesis. In summary, we have identified and characterized novel NAD+ homeostasis factors. These findings will expand our understanding of the molecular basis and regulation of NAD+ metabolism. © 2019 James Theoga Raj et al.

Citation

Christol James Theoga Raj, Trevor Croft, Padmaja Venkatakrishnan, Benjamin Groth, Gagandeep Dhugga, Timothy Cater, Su-Ju Lin. The copper-sensing transcription factor Mac1, the histone deacetylase Hst1, and nicotinic acid regulate de novo NAD+ biosynthesis in budding yeast. The Journal of biological chemistry. 2019 Apr 05;294(14):5562-5575