Novel regulatory function for the CCAAT-binding factor in Candida albicans.

Candida albicans is an opportunistic human pathogen that can sense environmental changes and respond by altering its cell morphology and physiology. A number of environmental factors have been shown to influence this dimorphic transition, including pH, starvation, serum, and amino acids. In this report, we investigate the function of the C. albicans CCAAT-binding factor. In Saccharomyces cerevisiae, this heterooligomeric transcriptional activator stimulates the expression of genes that encode proteins involved in respiration. To examine the function of this transcription factor in C. albicans, we cloned CaHAP5 and generated a hap5delta/hap5delta mutant of C. albicans. Using mobility shift studies, we identified four separate complexes from C. albicans cell extracts whose DNA-binding activities were abolished in the hap5delta/hap5delta mutant, suggesting that they represented sequence-specific CCAAT-binding complexes. We found that the C. albicans hap5delta homozygote was defective in hyphal development under a variety of conditions, and the mutant displayed a carbon source-dependent "hyperfilamentation" phenotype under certain growth conditions. In addition, the mRNA levels for two enzymes involved in respiration, encoded by COX5 and CYC1, were overexpressed in the hap5delta/hap5delta mutant when grown in medium containing amino acids as the sole carbon and nitrogen source. Thus, the C. albicans CCAAT-binding factor appeared to function as a repressor of genes encoding mitochondrial electron transport components, in contrast to its activator function in S. cerevisiae. These data provide the first evidence that the CCAAT-binding factor can act as a transcriptional repressor and raise new and interesting questions about how carbon metabolism is regulated in this opportunistic human pathogen.