Sch9 kinase integrates hypoxia and CO2 sensing to suppress hyphal morphogenesis in Candida albicans.

The yeast-hypha transition is an important virulence trait of Candida albicans. We report that the AGC kinase Sch9 prevents hypha formation specifically under hypoxia at high CO(2) levels. sch9 mutants showed no major defects in growth and stress resistance but a striking hyperfilamentous phenotype under hypoxia (<10% O(2)), although only in the presence of elevated CO(2) levels (>1%) and at temperatures of <37°C during surface growth. The sch9 hyperfilamentous phenotype was independent of Rim15 kinase and was recreated by inhibition of Tor1 kinase by rapamycin or caffeine in a wild-type strain, suggesting that Sch9 suppression requires Tor1. Caffeine inhibition also revealed that both protein kinase A isoforms, as well as transcription factors Czf1 and Ace2, are required to generate the sch9 mutant phenotype. Transcriptomal analyses showed that Sch9 regulates most genes solely under hypoxia and in the presence of elevated CO(2). In this environment, Sch9 downregulates genes encoding cell wall proteins and nutrient transporters, while under normoxia Sch9 and Tor1 coregulate a minor fraction of Sch9-regulated genes, e.g., by inducing glycolytic genes. Other than in Saccharomyces cerevisiae, both sch9 and rim15 mutants showed decreased chronological aging under normoxia but not under hypoxia, indicating significant rewiring of the Tor1-Sch9-Rim15 pathway in C. albicans. The results stress the importance of environmental conditions on Sch9 function and establish a novel response circuitry to both hypoxia and CO(2) in C. albicans, which suppresses hypha formation but also allows efficient nutrient uptake, metabolism, and virulence.

Transcriptional response of Candida albicans to hypoxia: linkage of oxygen sensing and Efg1p-regulatory networks.

The major human fungal pathogen, Candida albicans, colonizes different body sites, differing greatly in oxygen levels. Using whole-genome DNA microarrays, we analysed the transcriptomal response of C. albicans to hypoxia. In this condition, transcripts of genes involved in fermentative metabolism, including glycolytic genes, as well as hypha-specific genes, were up-regulated; in contrast, genes regulating oxidative metabolism were down-regulated. Although the morphogenetic and metabolic regulator Efg1p regulates these genes during normoxia, we found that Efg1p is not involved in their hypoxic regulation. Instead, Efg1p was specifically required for hypoxic expression or repression of subsets of genes. One class of hypoxia-regulated genes, encoding proteins involved in fatty acid biosynthesis, was dependent on Efg1p for maximal hypoxic expression, requiring Efg1p for transcriptional activation. During hypoxia, efg1 mutants contained lower levels of unsaturated fatty acids, while hyphal morphogenesis on solid media was significantly increased at temperatures <37 degrees C. These results suggest that during oxygen-limitation, Efg1p acts as a repressor of filamentation and as a positive regulator of fatty acid desaturation. We discuss that C. albicans responds to hypoxia largely by different mechanisms compared to budding yeast and that hypoxic adaptation requiring Efg1p is crucial for successful infection of human cells and tissues.