PRR1, a homolog of Aspergillus nidulans palF, controls pH-dependent gene expression and filamentation in Candida albicans.

Candida albicans is an opportunistic fungal pathogen of humans. It is the most frequent agent of superficial mucocutaneous infections, and, in immunocompromised hosts, it can cause life-threatening infections (38). The ability of this organism to cause infection depends, in part, on its ability to respond to changes in the pH of the environment (10). The pH response in C. albicans involves the differential expression of at least three genes, PHR1, PHR2, and PRA1 (34, 42, 44). PHR1 is an alkaline-expressed gene. It is highly expressed at between pH 7.0 and 8.0 but is not expressed at detectable levels at below pH 5.5 (42). PHR2 is an acid-expressed gene with an inverse pattern of expression (34). Mutations in PHR1 or PHR2 result in pH-conditional defects in growth, morphogenesis, and virulence (10, 34, 42). The significance of these genes and the pH response in the biology of C. albicans has prompted an investigation of the mechanisms controlling these responses. The control of pH-dependent gene expression has been most extensively studied with Aspergillus nidulans. Seven genes critical to this regulation have been identified. These include six pal genes, palA, -B, -C, -F, -H, and -I, and pacC (2, 9, 11, 12, 31, 37, 48). pacC, the terminal component of this regulatory pathway, encodes a transcription factor containing a zinc finger motif that directly induces expression of alkaline-expressed genes and indirectly represses acid-expressed genes (43, 48). The pacC protein, PacC, is synthesized in an inactive form that is proteolytically activated at alkaline pH (39). Proteolysis of PacC is dependent upon the pal genes, although their role in this process is unknown (2, 11, 12, 37, 39). The available data suggests that this response pathway is conserved, at least in part, in other fungi. In Yarrowia lipolytica a pacC homolog has been identified and shown to control alkaline-induced gene expression (27). In addition, four pal-like genes have been defined by mutation analysis (27). In Saccharomyces cerevisiae the pacC homolog, RIM101, was initially identified as controlling meiosis and haploid invasiveness (29, 46). More recently RIM101 and the yeast homology of palB, CPL1, have been implicated in a pH-dependent growth response of yeast (17). Genes homologous to palA and palI are also present in S. cerevisiae (11, 37). C. albicans sequences homologous to palA and pacC were recently reported (49). Null mutations in these genes affected morphological development, but it is not known if they affected the pH response (49). To investigate the regulation of pH-dependent gene expression in C. albicans, we have isolated and characterized PRR1 (for pH response regulator), the C. albicans homolog of palF. Expression of PRR1 was pH dependent, and mutants lacking PRR1 were defective in pH-dependent regulation of gene expression. PHR1 was no longer induced at alkaline pH, and PHR2 was no longer repressed. Thus, PRR1 is a component of the pH response pathway in C. albicans. In addition, mutation of PRR1 resulted in a medium-conditional loss of hyphal development. This defect was not related to the altered expression of PHR1, suggesting that this pathway controls development-specific functions. This control was shown to be independent of the EFG1-dependent regulation of hyphal development.