Candida glabrata, a human opportunistic pathogen is characterized by intrinsic, low susceptibility to fluconazole and a high capacity for acquiring high-level azole resistance. This is related to the elevated expression of genes belonging to the CgPdr1-governed regulon, comprising numerous genes, of which the multidrug ABC transporter-encoding CgCDR1, CgCDR2, CgSNQ2 are the best characterized. The function of certain PDR loci, such as CgRTA1 and CgRSB1 is poorly understood. These are homologs of ScRTA1 and ScRSB1 from Saccharomyces cerevisiae, members of the LTE family of plasma membrane proteins characteristic of fungi. While overproduced, they are involved in tolerance to 7-aminocholesterol or phytosphingosine, respectively. In this report we shed light on the differential regulation of CgRTA1 and CgRSB1 in C glabrata. CgRTA1 expression positively correlated with intrinsic azole tolerance in clinical isolates. In contrast to CgRSB1, a high induction of CgRTA1 was observed upon fluconazole exposure, which was accompanied by a parallel up-regulation of its transcriptional activator CgPDR1. Hypoxia or presence of ketoconazole, both leading to ergosterol depletion, resulted in increased level of CgRTA1 transcript, whereas CgRSB1 was highly responsive to mitochondrial dysfunction. On the other hand, the expression of CgRTA1 was suppressed during growth in pseudohyphae formation promoting media. Our results are the first report linking the divergent regulation of LTE family members and azole sensitivity in C glabrata. (C) 2013 Elsevier Inc. All rights reserved.