Evolutionary diversity of the control of the azole response by Tra1 across yeast species

Abstract

Tra1 is an essential co-activator protein of the yeast SAGA and NuA4 acetyltransferase complexes that regulate gene expression through multiple mechanisms including the acetylation of histone proteins. Tra1 is a pseudokinase of the PIKK family characterized by a C-terminal PI3K domain with no known kinase activity. However, mutations of specific arginine residues to glutamine in the PI3K domains (an allele termedtra1Q3) result in reduced growth and increased sensitivity to multiple stresses. In the opportunistic fungal pathogenCandida albicans, thetra1Q3allele reduces pathogenicity and increases sensitivity to the echinocandin antifungal drug caspofungin, which disrupts the fungal cell wall. Here, we found that loss of Tra1 function, in contrast to what is seen with caspofungin, increases tolerance to the azole class of antifungal drugs, which inhibits ergosterol synthesis. InC. albicans, tra1Q3increases expression of genes linked to azole resistance, such asERG11andCDR1. CDR1encodes a multidrug ABC transporter associated with efflux of multiple xenobiotics, including azoles. Consequently, cells carryingtra1Q3show reduced intracellular accumulation of fluconazole. In contrast, atra1Q3S. cerevisiaestrain displayed opposite phenotypes: decreased tolerance to azole, decreased expression of the efflux pumpPDR5and increased intracellular accumulation of fluconazole. Therefore, our data provide evidence that Tra1 differentially regulates the antifungal response across yeast species.