Translating biosynthetic gene clusters into fungal armor and weaponry

Keller, Nancy P.

doi:10.1038/nchembio.1897

Cited by 224 publications

(225 citation statements)

References 87 publications

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“…A hallmark of fungal secondary metabolites is that genes involved in production of a particular metabolite are clustered at a genetic locus, typically called a secondary metabolite cluster or biosynthetic gene cluster (BGC) (7). Aspergillus flavus and A. parasiticus contain nearly identical BGCs that are responsible for aflatoxin biosynthesis, while the genetic model A. nidulans harbors a similar BGC that produces the penultimate aflatoxin precursor sterigmatocystin (ST) (8).…”

Section: Importancementioning

confidence: 99%

Revitalization of a Forward Genetic Screen Identifies Three New Regulators of Fungal Secondary Metabolism in the Genus Aspergillus

Pfannenstiel

Zhao

Wortman

et al. 2017

mBio

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The study of aflatoxin in Aspergillus spp. has garnered the attention of many researchers due to aflatoxin's carcinogenic properties and frequency as a food and feed contaminant. Significant progress has been made by utilizing the model organism Aspergillus nidulans to characterize the regulation of sterigmatocystin (ST), the penultimate precursor of aflatoxin. A previous forward genetic screen identified 23 A. nidulans mutants involved in regulating ST production. Six mutants were characterized from this screen using classical mapping (five mutations in mcsA) and complementation with a cosmid library (one mutation in laeA). The remaining mutants were backcrossed and sequenced using Illumina and Ion Torrent sequencing platforms. All but one mutant contained one or more sequence variants in predicted open reading frames. Deletion of these genes resulted in identification of mutant alleles responsible for the loss of ST production in 12 of the 17 remaining mutants. Eight of these mutations were in genes already known to affect ST synthesis (laeA, mcsA, fluG, and stcA), while the remaining four mutations (in laeB, sntB, and hamI) were in previously uncharacterized genes not known to be involved in ST production. Deletion of laeB, sntB, and hamI in A. flavus results in loss of aflatoxin production, confirming that these regulators are conserved in the aflatoxigenic aspergilli. This report highlights the multifaceted regulatory mechanisms governing secondary metabolism in Aspergillus. Additionally, these data contribute to the increasing number of studies showing that forward genetic screens of fungi coupled with wholegenome resequencing is a robust and cost-effective technique.IMPORTANCE In a postgenomic world, reverse genetic approaches have displaced their forward genetic counterparts. The techniques used in forward genetics to identify loci of interest were typically very cumbersome and time-consuming, relying on Mendelian traits in model organisms. The current work was pursued not only to identify alleles involved in regulation of secondary metabolism but also to demonstrate a return to forward genetics to track phenotypes and to discover genetic pathways that could not be predicted through a reverse genetics approach. While identification of mutant alleles from whole-genome sequencing has been done before, here we illustrate the possibility of coupling this strategy with a genetic screen

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Section: Importancementioning

confidence: 99%

Revitalization of a Forward Genetic Screen Identifies Three New Regulators of Fungal Secondary Metabolism in the Genus Aspergillus

Pfannenstiel

Zhao

Wortman

et al. 2017

mBio

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“…Much of the interest is driven through a quest to find novel pharmaceuticals as many fungal SMs display valuable bioactivities, presumably evolved in their protective role against both biotic and abiotic stressors [1]. Furthermore, a subset of pathogenic fungi produces SMs that increase their virulence attributes on hosts.…”

Section: Introductionmentioning

confidence: 99%

Secondary metabolite arsenal of an opportunistic pathogenic fungus

Bignell

Cairns²,

Throckmorton

et al. 2016

Phil. Trans. R. Soc. B

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“…These compounds are involved in many different biological processes, including fungal development, intercellular communication, and interaction with other organisms in complex niches (1). Fungal secondary metabolites are of significant biotechnological and biopharmaceutical interest because they include antibiotics and other molecules/drugs relevant to human health (2). The biosynthesis of many secondary metabolites often involves large gene clusters with obscure regulatory networks and cryptic induction parameters (1,3).…”

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confidence: 99%

Regulatory cascade and biological activity of Beauveria bassiana oosporein that limits bacterial growth after host death

Fan

Liu

Keyhani

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

115

119

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The regulatory network and biological functions of the fungal secondary metabolite oosporein have remained obscure. Beauveria bassiana has evolved the ability to parasitize insects and outcompete microbial challengers for assimilation of host nutrients. A novel zinc finger transcription factor, BbSmr1 (B. bassiana secondary metabolite regulator 1), was identified in a screen for oosporein overproduction. Deletion of Bbsmr1 resulted in up-regulation of the oosporein biosynthetic gene cluster (OpS genes) and constitutive oosporein production. Oosporein production was abolished in double mutants of Bbsmr1 and a second transcription factor, OpS3, within the oosporein gene cluster (ΔBbsmr1ΔOpS3), indicating that BbSmr1 acts as a negative regulator of OpS3 expression. Real-time quantitative PCR and a GFP promoter fusion construct of OpS1, the oosporein polyketide synthase, indicated that OpS1 is expressed mainly in insect cadavers at 24-48 h after death. Bacterial colony analysis in B. bassiana-infected insect hosts revealed increasing counts until host death, with a dramatic decrease (∼90%) after death that correlated with oosporein production. In vitro studies verified the inhibitory activity of oosporein against bacteria derived from insect cadavers. These results suggest that oosporein acts as an antimicrobial compound to limit microbial competition on B. bassiana-killed hosts, allowing the fungus to maximally use host nutrients to grow and sporulate on infected cadavers.Beauveria bassiana | oosporein | biological role | transcription factor | fungal-bacterial competition

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Translating biosynthetic gene clusters into fungal armor and weaponry

Cited by 224 publications

References 87 publications

Revitalization of a Forward Genetic Screen Identifies Three New Regulators of Fungal Secondary Metabolism in the Genus Aspergillus

Revitalization of a Forward Genetic Screen Identifies Three New Regulators of Fungal Secondary Metabolism in the Genus Aspergillus

Secondary metabolite arsenal of an opportunistic pathogenic fungus

Regulatory cascade and biological activity of Beauveria bassiana oosporein that limits bacterial growth after host death

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