Dataset Information

Mevalonate governs interdependency of ergosterol and siderophore biosyntheses in the fungal pathogen Aspergillus fumigatus.

ABSTRACT: Aspergillus fumigatus is the most common airborne fungal pathogen for humans. In this mold, iron starvation induces production of the siderophore triacetylfusarinine C (TAFC). Here we demonstrate a link between TAFC and ergosterol biosynthetic pathways, which are both critical for virulence and treatment of fungal infections. Consistent with mevalonate being a limiting prerequisite for TAFC biosynthesis, we observed increased expression of 3-hydroxy-3-methyl-glutaryl (HMG)-CoA reductase (Hmg1) under iron starvation, reduced TAFC biosynthesis following lovastatin-mediated Hmg1 inhibition, and increased TAFC biosynthesis following Hmg1 overexpression. We identified enzymes, the acyl-CoA ligase SidI and the enoyl-CoA hydratase SidH, linking biosynthesis of mevalonate and TAFC, deficiency of which under iron starvation impaired TAFC biosynthesis, growth, oxidative stress resistance, and murine virulence. Moreover, inactivation of these enzymes alleviated TAFC-derived biosynthetic demand for mevalonate, as evidenced by increased resistance to lovastatin. Concordant with bilateral demand for mevalonate, iron starvation decreased the ergosterol content and composition, a phenotype that is mitigated in TAFC-lacking mutants.

SUBMITTER: Yasmin S

PROVIDER: S-EPMC3286978 | biostudies-literature | 2012 Feb

REPOSITORIES: biostudies-literature

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Mevalonate governs interdependency of ergosterol and siderophore biosyntheses in the fungal pathogen Aspergillus fumigatus.

Yasmin Sabiha S Alcazar-Fuoli Laura L Gründlinger Mario M Puempel Thomas T Cairns Timothy T Blatzer Michael M Lopez Jordi F JF Grimalt Joan O JO Bignell Elaine E Haas Hubertus H

Proceedings of the National Academy of Sciences of the United States of America 20111121 8

Aspergillus fumigatus is the most common airborne fungal pathogen for humans. In this mold, iron starvation induces production of the siderophore triacetylfusarinine C (TAFC). Here we demonstrate a link between TAFC and ergosterol biosynthetic pathways, which are both critical for virulence and treatment of fungal infections. Consistent with mevalonate being a limiting prerequisite for TAFC biosynthesis, we observed increased expression of 3-hydroxy-3-methyl-glutaryl (HMG)-CoA reductase (Hmg1) u ...[more]

PMID: 22106303

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Project description:Aspergillus fumigatus is a potentially deadly opportunistic fungal pathogen. Molecular studies have shaped our understanding of the genes, proteins, and molecules that contribute to A. fumigatus pathogenicity, but few studies have characterized genome-wide patterns of genetic variation at the population level. Of A. fumigatus genomic studies to-date, most focus mainly on single nucleotide polymorphisms and large structural variants, while overlooking the contribution of copy number variation (CNV). CNV is a class of small structural variation defined as loci that vary in their number of copies between individuals due to duplication, gain, or deletion. CNV can influence phenotype, including fungal virulence. In the present study, we characterized the population genomic patterns of CNV in a diverse collection of 71 A. fumigatus isolates using publicly available sequencing data. We used genome-wide single nucleotide polymorphisms to infer the population structure of these isolates and identified three populations consisting of at least 8 isolates. We then computationally predicted genome-wide CNV profiles for each isolate and conducted analyses at the species-, population-, and individual levels. Our results suggest that CNV contributes to genetic variation in A. fumigatus, with ~10% of the genome being CN variable. Our analysis indicates that CNV is non-randomly distributed across the A. fumigatus genome, and is overrepresented in subtelomeric regions. Analysis of gene ontology categories in genes that overlapped CN variants revealed an enrichment of genes related to transposable element and secondary metabolism functions. We further identified 72 loci containing 33 genes that showed divergent copy number profiles between the three A. fumigatus populations. Many of these genes encode proteins that interact with the cell surface or are involved in pathogenicity. Our results suggest that CNV is an important source of genetic variation that could account for some of the phenotypic differences between A. fumigatus populations and isolates.

Project description:Biosynthesis of many ecologically important secondary metabolites (SMs) in filamentous fungi is controlled by several global transcriptional regulators, like the chromatin modifier LaeA, and tied to both development and vegetative growth. In Aspergillus molds, asexual development is regulated by the BrlA > AbaA > WetA transcriptional cascade. To elucidate BrlA pathway involvement in SM regulation, we examined the transcriptional and metabolic profiles of ΔbrlA, ΔabaA, and ΔwetA mutant and wild-type strains of the human pathogen Aspergillus fumigatus. We find that BrlA, in addition to regulating production of developmental SMs, regulates vegetative SMs and the SrbA-regulated hypoxia stress response in a concordant fashion to LaeA. We further show that the transcriptional and metabolic equivalence of the ΔbrlA and ΔlaeA mutations is mediated by an LaeA requirement preventing heterochromatic marks in the brlA promoter. These results provide a framework for the cellular network regulating not only fungal SMs but diverse cellular processes linked to virulence of this pathogen. IMPORTANCE Filamentous fungi produce a spectacular variety of small molecules, commonly known as secondary or specialized metabolites (SMs), which are critical to their ecologies and lifestyles (e.g., penicillin, cyclosporine, and aflatoxin). Elucidation of the regulatory network that governs SM production is a major question of both fundamental and applied research relevance. To shed light on the relationship between regulation of development and regulation of secondary metabolism in filamentous fungi, we performed global transcriptomic and metabolomic analyses on mutant and wild-type strains of the human pathogen Aspergillus fumigatus under conditions previously shown to induce the production of both vegetative growth-specific and asexual development-specific SMs. We find that the gene brlA, previously known as a master regulator of asexual development, is also a master regulator of secondary metabolism and other cellular processes. We further show that brlA regulation of SM is mediated by laeA, one of the master regulators of SM, providing a framework for the cellular network regulating not only fungal SMs but diverse cellular processes linked to virulence of this pathogen.

Dataset Information

Mevalonate governs interdependency of ergosterol and siderophore biosyntheses in the fungal pathogen Aspergillus fumigatus.

Publications

Mevalonate governs interdependency of ergosterol and siderophore biosyntheses in the fungal pathogen Aspergillus fumigatus.

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