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SREBP coordinates iron and ergosterol homeostasis to mediate triazole drug and hypoxia responses in the human fungal pathogen Aspergillus fumigatus.
PLoS Genet 2011; 7(12):e1002374PG

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+Show Affiliations

Division of Molecular Biology/Biocenter, Innsbruck Medical University, Innsbruck, Austria.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

22144905

Citation

Blatzer, Michael, et al. "SREBP Coordinates Iron and Ergosterol Homeostasis to Mediate Triazole Drug and Hypoxia Responses in the Human Fungal Pathogen Aspergillus Fumigatus." PLoS Genetics, vol. 7, no. 12, 2011, pp. e1002374.
Blatzer M, Barker BM, Willger SD, et al. SREBP coordinates iron and ergosterol homeostasis to mediate triazole drug and hypoxia responses in the human fungal pathogen Aspergillus fumigatus. PLoS Genet. 2011;7(12):e1002374.
Blatzer, M., Barker, B. M., Willger, S. D., Beckmann, N., Blosser, S. J., Cornish, E. J., ... Cramer, R. A. (2011). SREBP coordinates iron and ergosterol homeostasis to mediate triazole drug and hypoxia responses in the human fungal pathogen Aspergillus fumigatus. PLoS Genetics, 7(12), pp. e1002374. doi:10.1371/journal.pgen.1002374.
Blatzer M, et al. SREBP Coordinates Iron and Ergosterol Homeostasis to Mediate Triazole Drug and Hypoxia Responses in the Human Fungal Pathogen Aspergillus Fumigatus. PLoS Genet. 2011;7(12):e1002374. PubMed PMID: 22144905.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - SREBP coordinates iron and ergosterol homeostasis to mediate triazole drug and hypoxia responses in the human fungal pathogen Aspergillus fumigatus. AU - Blatzer,Michael, AU - Barker,Bridget M, AU - Willger,Sven D, AU - Beckmann,Nicola, AU - Blosser,Sara J, AU - Cornish,Elizabeth J, AU - Mazurie,Aurelien, AU - Grahl,Nora, AU - Haas,Hubertus, AU - Cramer,Robert A, Y1 - 2011/12/01/ PY - 2011/05/26/received PY - 2011/09/22/accepted PY - 2011/12/7/entrez PY - 2011/12/7/pubmed PY - 2012/3/2/medline SP - e1002374 EP - e1002374 JF - PLoS genetics JO - PLoS Genet. VL - 7 IS - 12 N2 - 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. SN - 1553-7404 UR - https://www.unboundmedicine.com/medline/citation/22144905/SREBP_coordinates_iron_and_ergosterol_homeostasis_to_mediate_triazole_drug_and_hypoxia_responses_in_the_human_fungal_pathogen_Aspergillus_fumigatus_ L2 - http://dx.plos.org/10.1371/journal.pgen.1002374 DB - PRIME DP - Unbound Medicine ER -