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An Aspergillus nidulans bZIP response pathway hardwired for defensive secondary metabolism operates through aflR.

ABSTRACT: The eukaryotic bZIP transcription factors are critical players in organismal response to environmental challenges. In fungi, the production of secondary metabolites (SMs) is hypothesized as one of the responses to environmental insults, e.g. attack by fungivorous insects, yet little data to support this hypothesis exists. Here we establish a mechanism of bZIP regulation of SMs through RsmA, a recently discovered YAP-like bZIP protein. RsmA greatly increases SM production by binding to two sites in the Aspergillus nidulans AflR promoter region, a C6 transcription factor known for activating production of the carcinogenic and anti-predation SM, sterigmatocystin. Deletion of aflR in an overexpression rsmA (OE:rsmA) background not only eliminates sterigmatocystin production but also significantly reduces asperthecin synthesis. Furthermore, the fungivore, Folsomia candida, exhibited a distinct preference for feeding on wild type rather than an OE:rsmA strain. RsmA may thus have a critical function in mediating direct chemical resistance against predation. Taken together, these results suggest RsmA represents a bZIP pathway hardwired for defensive SM production.

SUBMITTER: Yin WB

PROVIDER: S-EPMC3288630 | biostudies-literature | 2012 Mar

REPOSITORIES: biostudies-literature

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An Aspergillus nidulans bZIP response pathway hardwired for defensive secondary metabolism operates through aflR.

Yin Wen-Bing WB Amaike Saori S Wohlbach Dana J DJ Gasch Audrey P AP Chiang Yi-Ming YM Wang Clay C C CC Bok Jin Woo JW Rohlfs Marko M Keller Nancy P NP

Molecular microbiology 20120210 5

The eukaryotic bZIP transcription factors are critical players in organismal response to environmental challenges. In fungi, the production of secondary metabolites (SMs) is hypothesized as one of the responses to environmental insults, e.g. attack by fungivorous insects, yet little data to support this hypothesis exists. Here we establish a mechanism of bZIP regulation of SMs through RsmA, a recently discovered YAP-like bZIP protein. RsmA greatly increases SM production by binding to two sites ...[more]

PMID: 22283524

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Project description:The filamentous fungus Aspergillus nidulans has been a primary workhorse used to understand fungal genetics. Much of this work has focused on elucidating the genetics of biosynthetic gene clusters (BGCs) and the secondary metabolites (SMs) they produce. SMs are both niche defining in fungi and of great economic importance to humans. Despite the focus on A. nidulans, very little is known about the natural diversity in secondary metabolism within this species. We determined the BGC content and looked for evolutionary patterns in BGCs from whole-genome sequences of two clinical isolates and the A4 reference genome of A. nidulans Differences in BGC content were used to explain SM profiles determined using liquid chromatography-high-resolution mass spectrometry. We found that in addition to genetic variation of BGCs contained by all isolates, nine BGCs varied by presence/absence. We discovered the viridicatumtoxin BGC in A. nidulans and suggest that this BGC has undergone a horizontal gene transfer from the Aspergillus section Nigri lineage into Penicillium sometime after the sections Nigri and Nidulantes diverged. We identified the production of viridicatumtoxin and several other compounds previously not known to be produced by A. nidulans One isolate showed a lack of sterigmatocystin production even though it contained an apparently intact sterigmatocystin BGC, raising questions about other genes and processes known to regulate this BGC. Altogether, our work uncovers a large degree of intraspecies diversity in BGC and SM production in this genetic model species and offers new avenues to understand the evolution and regulation of secondary metabolism.IMPORTANCE Much of what we know about the genetics underlying secondary metabolite (SM) production and the function of SMs in the model fungus Aspergillus nidulans comes from a single reference genome. A growing body of research indicates the importance of biosynthetic gene cluster (BGC) and SM diversity within a species. However, there is no information about the natural diversity of secondary metabolism in A. nidulans We discovered six novel clusters that contribute to the considerable variation in both BGC content and SM production within A. nidulans We characterize a diverse set of mutations and emphasize how findings of single nucleotide polymorphisms (SNPs), deletions, and differences in evolutionary history encompass much of the variation observed in nonmodel systems. Our results emphasize that A. nidulans may also be a strong model to use within-species diversity to elucidate regulatory cross talk, fungal ecology, and drug discovery systems.

Project description:BackgroundThe inherent potential of filamentous fungi, especially of Ascomycota, for producing diverse bioactive metabolites remains largely silent under standard laboratory culture conditions. Innumerable strategies have been described to trigger their production, one of the simplest being manipulation of the growth media composition. Supplementing media with ionic liquids surprisingly enhanced the diversity of extracellular metabolites generated by penicillia. This finding led us to evaluate the impact of ionic liquids' stimuli on the fungal metabolism in Aspergillus nidulans and how it reflects on the biosynthesis of secondary metabolites (SMs).ResultsWhole transcriptional profiling showed that exposure to 0.7 M cholinium chloride or 1-ethyl-3-methylimidazolium chloride dramatically affected expression of genes encoding both primary and secondary metabolism. Both ionic liquids apparently induced stress responses and detoxification mechanisms but response profiles to each stimulus were unique. Primary metabolism was up-regulated by choline, but down-regulated by 1-ethyl-3-methylimidazolium chloride; both stimulated production of acetyl-CoA (key precursor to numerous SMs) and non proteinogenic amino acids (building blocks of bioactive classes of SMs). In total, twenty one of the sixty six described backbone genes underwent up-regulation. Accordingly, differential analysis of the fungal metabolome showed that supplementing growth media with ionic liquids resulted in ca. 40 differentially accumulated ion masses compared to control conditions. In particular, it stimulated production of monodictyphenone and orsellinic acid, otherwise cryptic. Expression levels of genes encoding corresponding polyketide biosynthetic enzymes (i.e. backbone genes) increased compared to control conditions. The corresponding metabolite extracts showed increased cell polarity modulation potential in an ex vivo whole tissue assay (The lial Live Targeted Epithelia; theLiTE™).ConclusionsIonic liquids, a diverse class of chemicals composed solely of ions, can provide an unexpected means to further resolve the diversity of natural compounds, guiding discovery of fungal metabolites with clinical potential.

Dataset Information

An Aspergillus nidulans bZIP response pathway hardwired for defensive secondary metabolism operates through aflR.

Publications

An Aspergillus nidulans bZIP response pathway hardwired for defensive secondary metabolism operates through aflR.

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