부산대학교 도서관

Heme (iron-protoporphyrin IX) is an essential but potentially toxic cellular cofactor. While most organisms are heme prototrophs, many microorganisms can utilize environmental heme as iron source. The pathogenic yeast Candida albicans can utilize host heme in the iron-poor host environment, using an extracellular cascade of soluble and anchored hemophores, and plasma membrane ferric reductase-like proteins. To gain additional insight into the C. albicans heme uptake pathway, we performed an unbiased genetic selection for mutants resistant to the toxic heme analog Ga3+-protoporphyrin IX at neutral pH, and a secondary screen for inability to utilize heme as iron source. Among the mutants isolated were the genes of the pH-responsive RIM pathway, and a zinc finger transcription factor related to S. cerevisiae HAP1. In the presence of hemin in the medium, C. albicans HAP1 is induced, the Hap1 protein is stabilized and Hap1-GFP localizes to the nucleus. In the hap1 mutant, cytoplasmic heme levels are elevated, while influx of extracellular heme is lower. Gene expression analysis indicated that in the presence of extracellular hemin, Hap1 activates the heme oxygenase HMX1, which breaks down excess cytoplasmic heme, while at the same time it also activates all the known heme uptake genes. These results indicate that Hap1 is a heme-responsive transcription factor that plays a role both in cytoplasmic heme homeostasis and in utilization of extracellular heme. The induction of heme uptake genes by C. albicans Hap1 under iron satiety indicates that preferential utilization of host heme can be a dietary strategy in a heme prototroph. Author summary: The yeast Candida albicans is a human commensal organism, as well as an important opportunistic systemic pathogen. During tissue invasion, systemic pathogens are confronted with iron scarcity, which they can overcome by scavenging host heme as iron source. It was however not known whether C. albicans can sense the presence of host heme independently of iron sensing. Using a forward genetics approach, we identified a transcription factor that regulates both homeostasis of internal heme and uptake of external heme. This transcription factor allows activation of the heme uptake pathway even in iron-rich medium, suggesting that heme can be a preferred iron source over elemental iron, and that heme prototrophs can scavenge host heme as a source for cellular heme. [ABSTRACT FROM AUTHOR]