Abstract
Iron is essential for a wide range of cellular processes. Here we show that the bZIP-type regulator HapX is indispensable for the transcriptional remodeling required for adaption to iron starvation in the opportunistic fungal pathogen Aspergillus fumigatus. HapX represses iron-dependent and mitochondrial-localized activities including respiration, TCA cycle, amino acid metabolism, iron-sulfur-cluster and heme biosynthesis. In agreement with the impact on mitochondrial metabolism, HapX-deficiency decreases resistance to tetracycline and increases mitochondrial DNA content. Pathways positively affected by HapX include production of the ribotoxin AspF1 and siderophores, which are known virulence determinants. Iron starvation causes a massive remodeling of the amino acid pool and HapX is essential for the coordination of the production of siderophores and their precursor ornithine. Consistent with HapX-function being limited to iron depleted conditions and A. fumigatus facing iron starvation in the host, HapX-deficiency causes significant attenuation of virulence in a murine model of aspergillosis. Taken together, this study demonstrates that HapX-dependent adaption to conditions of iron starvation is crucial for virulence of A. fumigatus.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptation, Psychological*
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Allergens
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Amino Acids / metabolism
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Animals
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Anti-Bacterial Agents / pharmacology
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Antigens, Plant / genetics
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Antigens, Plant / metabolism
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Aspergillosis / genetics
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Aspergillosis / metabolism*
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Aspergillosis / virology*
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Aspergillus fumigatus / pathogenicity*
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Basic-Leucine Zipper Transcription Factors / genetics
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Basic-Leucine Zipper Transcription Factors / metabolism*
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Biomarkers / metabolism
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Blotting, Northern
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DNA, Mitochondrial / genetics
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Disease Models, Animal
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Drug Resistance, Fungal / genetics
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Fungal Proteins / genetics
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Fungal Proteins / metabolism
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GATA Transcription Factors / genetics
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GATA Transcription Factors / metabolism
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Gene Expression Profiling
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Gene Expression Regulation, Fungal
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Iron Deficiencies*
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Mice
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Oligonucleotide Array Sequence Analysis
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Ornithine / metabolism
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RNA, Messenger / genetics
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Repressor Proteins / genetics
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Repressor Proteins / metabolism
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Reverse Transcriptase Polymerase Chain Reaction
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Siderophores / physiology
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Survival Rate
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Tetracycline / pharmacology
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Virulence / physiology*
Substances
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ASPF1 protein, Aspergillus fumigatus
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Allergens
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Amino Acids
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Anti-Bacterial Agents
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Antigens, Plant
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Basic-Leucine Zipper Transcription Factors
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Biomarkers
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DNA, Mitochondrial
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Fungal Proteins
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GATA Transcription Factors
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RNA, Messenger
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Repressor Proteins
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SREA protein, Aspergillus nidulans
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Siderophores
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Ornithine
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Tetracycline