title: 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 ΔsrbA 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 ΔsrbA background was able to partially rescue the hypoxia growth, triazole drug susceptibility, and decrease in ergosterol content phenotypes of ΔsrbA. 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.
authors.affiliation: Division of Molecular Biology/Biocenter, Innsbruck Medical University, Innsbruck, Austria.
authors.forename: Michael
authors.initials: M
authors.lastname: Blatzer
authors.forename: Bridget M
authors.initials: BM
authors.lastname: Barker
authors.forename: Sven D
authors.initials: SD
authors.lastname: Willger
authors.forename: Nicola
authors.initials: N
authors.lastname: Beckmann
authors.forename: Sara J
authors.initials: SJ
authors.lastname: Blosser
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Cornish
authors.forename: Aurelien
authors.initials: A
authors.lastname: Mazurie
authors.forename: Nora
authors.initials: N
authors.lastname: Grahl
authors.forename: Hubertus
authors.initials: H
authors.lastname: Haas
authors.forename: Robert A
authors.initials: RA
authors.lastname: Cramer
mesh_terms: D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology*; D001232:Aspergillus fumigatus / Q000187:drug effects* / Q000472:pathogenicity; D025141:Drug Resistance, Fungal / Q000235:genetics; D004875:Ergosterol / Q000378:metabolism*; D015966:Gene Expression Regulation, Fungal / Q000235:genetics; D006706:Homeostasis; D006801:Humans; D007501:Iron / Q000378:metabolism*; D008172:Lung Diseases, Fungal / Q000188:drug therapy / Q000235:genetics; D051379:Mice; D020411:Oligonucleotide Array Sequence Analysis; D017262:Siderophores / Q000378:metabolism; D051779:Sterol Regulatory Element Binding Proteins / Q000235:genetics / Q000378:metabolism*; D014230:Triazoles / Q000494:pharmacology
chemical_list: D000935:Antifungal Agents; D017262:Siderophores; D051779:Sterol Regulatory Element Binding Proteins; D014230:Triazoles; D007501:Iron; D004875:Ergosterol