Abstract
The CCAAT-motif is ubiquitous in promoters of eukaryotic genomes. The CCAAT-binding complex (CBC), which is conserved from fungi to plants, to mammals, specifically recognizes the CCAAT-motif and modulates transcription directly or in cooperation with other transcription factors. In Candida albicans, Hap43 was identified to interact with CBC. In this study, the function of Hap43 was first characterized. The results demonstrated that Hap43 is a low iron–induced transcription factor and is responsible for repression of genes encoding iron-dependent proteins in response to iron deprivation. Iron deprived conditions can induce the nuclear localization of Hap43. Moreover, Hap43-mediated regulation was shown to depend on the presence of CBC. However, it is unclear whether CBC can function independently of Hap43. The Hap43-independent role of CBC in C. albicans was further explored and the results showed that CBC acts as a novel regulator of virulence traits. Genome-wide transcriptional profiling suggested that CBC contributes to negative regulation of ribosome biogenesis and translation and positive regulation of nitrogen starvation-mediated responses. CBC was also required for low nitrogen–induced filamentation, utilization of nitrogen sources from proteins, and repression of flocculation phenotype. Interestingly, epistasis analyses suggested that CBC is an important downstream effector of Rhb1-TOR signaling and controls low nitrogen–induced filamentation via the Mep2-Ras1-PKA/MAPK pathway. Finally, deletion of HAP43 and CBC genes attenuated C. albicans virulence. This study therefore highlights the crucial role of C. albicans CBC in regulating multiple virulence traits in response to environmental perturbations. These findings not only provide basic information for C. albicans per se but also may increase our understanding of the pathogenesis of other human fungal pathogens.