NuA4 Lysine Acetyltransferase Complex Contributes to Phospholipid Homeostasis inSaccharomyces cerevisiae

Abstract

Actively proliferating cells constantly monitor and readjust their metabolic pathways to ensure the replenishment of phospholipids necessary for membrane biogenesis and intracellular trafficking. In Saccharomyces cerevisiae, multiple studies have suggested that the lysine acetyltransferase complex NuA4 plays a role in phospholipid homeostasis. For one, NuA4 mutants induce the expression of the inositol-3-phosphate synthase gene, INO1, which leads to excessive accumulation of inositol, a key metabolite used for phospholipid biosynthesis. Additionally, NuA4 mutants also display negative genetic interactions with sec14-1ts, a mutant of a lipid-binding gene responsible for phospholipid remodeling of the Golgi. Here, using a combination of genetics and transcriptional profiling, we explore the connections between NuA4, inositol, and Sec14. Surprisingly, we found that NuA4 mutants did not suppress but rather exacerbated the growth defects of sec14-1ts under inositol-depleted conditions. Transcriptome studies reveal that while loss of the NuA4 subunit EAF1 in sec14-1ts does derepress INO1 expression, it does not derepress all inositol/choline-responsive phospholipid genes, suggesting that the impact of Eaf1 on phospholipid homeostasis extends beyond inositol biosynthesis. In fact, we find that NuA4 mutants have impaired lipid droplet levels and through genetic and chemical approaches, we determine that the genetic interaction between sec14-1ts and NuA4 mutants potentially reflects a role for NuA4 in fatty acid biosynthesis. Altogether, our work identifies a new role for NuA4 in phospholipid homeostasis.

Phenomic screen identifies a role for the yeast lysine acetyltransferase NuA4 in the control of Bcy1 subcellular localization, glycogen biosynthesis, and mitochondrial morphology

“…Though non-essential, the EAF1 subunit is a critical scaffolding protein required to maintain the complete NuA4 complex [ 16 , 19 ]. Yeast cells deficient for Eaf1 are viable but lose much of the targeting of the catalytic Esa1 subunit, making the eaf1Δ mutant an excellent genetic model system to identify the biological roles and protein targets of NuA4 [ 16 , 18 , 20 , 21 ]. Alternatively, NuA4 function can be probed using the temperature sensitive mutation, esa1-ts ( esa1-L245P ), which reduces the acetylation activity of Esa1 at increased temperatures [ 2 , 17 , 22 ].…”

Octopus-toolkit: a workflow to automate mining of public epigenomic and transcriptomic next-generation sequencing data

“…Further experimental validation will reveal the molecular mechanism underlying the recruitment of the NuA4 complex. In support of this, recent studies ( 20 , 21 ) demonstrated the new mechanistic dissection between the NuA4 complex and phospholipid homeostasis, further enforcing the suggested direct link between ESA1 and OPI1.…”

Translational control of lipogenesis links protein synthesis and phosphoinositide signaling with nuclear division

“…De-repressing translation of ACC1 and FAS1 corrects mitotic phenotypes of sec14 mutants Conditional sec14 mutants proliferate at 25°C, but not at 37°C (Novick et al, 1980) . Furthermore, inhibition of lipogenesis by cerulenin exacerbates the temperature sensitivity of sec14-1 cells (Dacquay et al, 2017) . Whereas the cerulenin effect is a rather non-specific phenotype (Lee et al, 2014) , this observation raised the question of whether the increased lipogenesis in uORFm-ACC1,FAS1 cells could suppress the temperature-sensitive proliferation of sec14-1 cells.…”