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The metalloreductase FreB is involved in adaptation of Aspergillus fumigatus to iron starvation.

ABSTRACT: Aspergillus fumigatus employs two high affinity iron uptake mechanisms, siderophore mediated iron uptake and reductive iron assimilation (RIA). The A. fumigatus genome encodes 15 putative metalloreductases (MR) but the ferrireductases involved in RIA remained elusive so far. Expression of the MR FreB was found to be transcriptionally repressed by iron via SreA, a repressor of iron acquisition during iron sufficiency, indicating a role in iron metabolism. FreB-inactivation by gene deletion was phenotypically largely inconspicuous unless combined with inactivation of the siderophore system, which then decreased growth rate, surface ferrireductase activity and oxidative stress resistance during iron starvation. This study also revealed that loss of copper-independent siderophore-mediated iron uptake increases sensitivity of A. fumigatus to copper starvation due to copper-dependence of RIA.

SUBMITTER: Blatzer M

PROVIDER: S-EPMC3188701 | biostudies-literature | 2011 Nov

REPOSITORIES: biostudies-literature

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The metalloreductase FreB is involved in adaptation of Aspergillus fumigatus to iron starvation.

Blatzer Michael M Binder Ulrike U Haas Hubertus H

Fungal genetics and biology : FG & B 20110805 11

Aspergillus fumigatus employs two high affinity iron uptake mechanisms, siderophore mediated iron uptake and reductive iron assimilation (RIA). The A. fumigatus genome encodes 15 putative metalloreductases (MR) but the ferrireductases involved in RIA remained elusive so far. Expression of the MR FreB was found to be transcriptionally repressed by iron via SreA, a repressor of iron acquisition during iron sufficiency, indicating a role in iron metabolism. FreB-inactivation by gene deletion was ph ...[more]

PMID: 21840411

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Project description:Iron is an essential cofactor for a wide range of cellular processes. Previous studies have shown that siderophore-mediated uptake and intracellular handling of iron are crucial for virulence of Aspergillus fumigatus. Here we show that the bzip-type transcription factor HapX plays a crucial role in the transcriptional remodeling required for adaption to iron starvation in this opportunistic fungal pathogen. HapX was found to be interconnected in a negative feed-back loop with the previously identified iron regulator SreA: SreA repressed expression of hapX during iron sufficiency and HapX repressed sreA during iron starvation. Genome-wide transcriptional profiling and analysis of selected metabolites (protophorphyrine IX, siderophores and amino acids) indicated extensive metabolic remodeling in response to iron starvation. HapX was found to participate in both, repression and activation of genes during iron starvation. HapX was in particular required for repression of iron-dependent and mitochondrial-localized activities including respiration, TCA cycle, amino acid metabolism, iron-sulfur-cluster biosynthesis and heme biosynthesis. Pathways positively affected by HapX included production of siderophores and the ribotoxin and major allergen AspF1. Analysis of the free amino acid pool revealed HapX-dependent coordination of the production of siderophores with the supply of its precursor ornithine. Consistent with the hapX expression pattern, HapX-deficiency was deleterious with respect to growth rate and conidiation during iron depleted but not iron-replete conditions. HapX-deficiency caused significant attenuation of virulence in a murine model aspergillosis underlining that A. fumigatus faces iron starvation in the host and that the HapX-dependent metabolic reprogramming is therefore crucial for virulence. A. fumigatus 293 and hapX mutants were grown in the presence and absence of iron and in cultures shifted from no iron to iron-containing conditions after 1 h incubation. Hybridizations were performed with biological replicates for wt vs hapX +/- iron. For the iron-shift experiments, there were biological replicates for wt in both conditions and for hapX in -iron but there was only a single biological sample for hapX iron-shift sample. All hybs were performed with flip-dye pairs.

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The metalloreductase FreB is involved in adaptation of Aspergillus fumigatus to iron starvation.

Publications

The metalloreductase FreB is involved in adaptation of Aspergillus fumigatus to iron starvation.

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