NuA4 is important for the Sec14 bypass phenotype and lipid droplet formation through a role within the fatty acid biosynthesis pathway

Actively proliferating cells must constantly monitor and re-adjust their metabolic pathways to ensure phospholipid homeostasis for the replenishment of membranes and intracellular trafficking. Multiple studies have suggested that the lysine acetyltransferase NuA4 has a role in fine-tuning phospholipid metabolism in Saccharomyces cerevisiae, however the role of NuA4 in phospholipid homeostasis remains poorly defined. NuA4 mutants have increased gene expression of inositol-3-phosphate synthase, INO1 and overproduce inositol. NuA4 mutants are also display synthetic sickness with a mutant of the lipid remodeling gene SEC14. Here using a combination of genetics and transcriptional profiling, we explore the connections between NuA4, inositol and Sec14. We found that NuA4 mutants exacerbated the inositol auxotrophy of sec14-1ts. Transcriptome studies reveal that loss of the NuA4 subunit EAF1 in sec14-1ts depresses INO1 expression but not all inositol/choline responsive phospholipid genes. This suggests deltaeaf1 cells are defective in coordinating phospholipid homeostasis beyond inositol production. In fact, we discovered that deltaeaf1 cells have significantly lower lipid droplet levels and that inhibition of the fatty acid biosynthesis pathway increased the growth defect of sec14-1ts to a similar extent as untreated sec14-1ts deltaeaf1 Altogether, our work identifies a role for NuA4 as a critical mediator of phospholipid metabolism, potentially as positive regulator of fatty acid biosynthesis.