Characterizing a role for NuA4 in the regulation of ergosterol in yeast

Abstract

NuA4 is an essential lysine acetyltransferase (KAT) in yeast and is homologous to Tip60, a disease relevant protein complex in mammalian cells. As our lab and others have recently identified a novel role for NuA4 in lipid regulation, we performed a global lipidomic analysis. We determined that two mutants of NuA4, a temperature sensitive mutant of the catalytic subunit (esa1-ts) and deletion of the non-essential scaffolding subunit (eaf1Δ), have an increase in the relative abundance of ergosteryl esters, the yeast equivalent to cholesteryl esters. Following this discovery, we have also found that the NuA4 mutants have altered sensitivity to many compounds which target ergosterol synthesis and ergosterol in the membrane. This suggests that ergosterol regulation in NuA4 mutants may be altered. We are working to measure ergosterol directly in these mutants as well as to determine how NuA4 may affect ergosterol regulation in the cell. Specifically, we are using the deletion mutant array, a collection of yeast strains with each gene deleted, to look for genes that reverse the sensitivity of NuA4 mutants to ergosterol targeting compounds such as Amphotericin B and Nystatin. Overall, this study aims to characterize changes in ergosterol regulation in yeast NuA4 mutants. Given the exceptional conservation of KAT function across eukaryotes, this may provide insight into understanding the biological roles of Tip60 in lipid regulation and the cellular consequences of its deregulation in disease.