SREBP Coordinates Iron and Ergosterol Homeostasis to Mediate Triazole Drug and Hypoxia Responses in the Human Fungal Pathogen Aspergillus fumigatus

Abstract

Sterol regulatory element binding proteins (SREBPs) are a class of basic helix-loop-helix transcription factors that regulate diverse cellular responses in eukaryotes. Adding to the recognized importance of SREBPs in human health, SREBPs in the human fungal pathogens Cryptococcus neoformans and Aspergillus fumigatus are required for fungal virulence and susceptibility to triazole antifungal drugs. To date, the exact mechanism(s) behind the role of SREBP in these observed phenotypes is not clear. Here, we report that A. fumigatus SREBP, SrbA, mediates regulation of iron acquisition in response to hypoxia and low iron conditions. To further define SrbA's role in iron acquisition in relation to previously studied fungal regulators of iron metabolism, SreA and HapX, a series of mutants were generated in the Δ srbA background. These data suggest that SrbA is activated independently of SreA and HapX in response to iron limitation, but that HapX mRNA induction is partially dependent on SrbA. Intriguingly, exogenous addition of high iron or genetic deletion of sreA in the Δ srbA background was able to partially rescue the hypoxia growth, triazole drug susceptibility, and decrease in ergosterol content phenotypes of Δ srbA. Thus, we conclude that the fungal SREBP, SrbA, is critical for coordinating genes involved in iron acquisition and ergosterol biosynthesis under hypoxia and low iron conditions found at sites of human fungal infections. These results support a role for SREBP–mediated iron regulation in fungal virulence, and they lay a foundation for further exploration of SREBP's role in iron homeostasis in other eukaryotes.

Author Summary

Advances in medical technologies over the past several years have led to an increasing population of patients susceptible to fungal infections. Despite the immunocompromised condition of most patients that acquire these infections, the majority are caused by three fungi: Candida albicans, Cryptococcus neoformans, and Aspergillus fumigatus. Of these, A. fumigatus is least studied, and the ability of this fungus to cause lethal disease in these patients needs more examination. We previously identified a transcription factor in the sterol-regulatory element binding protein family, SrbA, in this pathogenic mold that is critical for virulence and susceptibility to triazole antifungal drugs. The mechanism by which SrbA mediates these clinically relevant phenotypes is unclear. Here, we discover that SrbA is critical for regulation of iron metabolism, particularly through regulation of siderophore production and uptake. We find that A. fumigatus requires iron uptake during the initial phases of adaptation to hypoxic microenvironments and that restoration of iron uptake in the srbA null mutant is able to partially restore the hypoxia growth defect and triazole susceptibility of this mutant. Taken together, our results identify a new role for this important fungal SREBP and give new insights into the clinically relevant roles of SrbA.