Abstract
Aspergillus fumigatus is the causative agent of invasive aspergillosis, leading to infection-related mortality in immunocompromised patients. We previously showed that the conserved and unique-to-fungi veA gene affects different cell processes such as morphological development, gliotoxin biosynthesis and protease activity, suggesting a global regulatory effect on the genome of this medically relevant fungus. In this study, RNA sequencing analysis revealed that veA controls the expression of hundreds of genes in A. fumigatus, including those comprising more than a dozen known secondary metabolite gene clusters. Chemical analysis confirmed that veA controls the synthesis of other secondary metabolites in this organism in addition to gliotoxin. Among the secondary metabolite gene clusters regulated by veA is the elusive but recently identified gene cluster responsible for the biosynthesis of fumagillin, a meroterpenoid known for its anti-angiogenic activity by binding to human methionine aminopeptidase 2. The fumagillin gene cluster contains a veA-dependent regulatory gene, fumR (Afu8g00420), encoding a putative C6 type transcription factor. Deletion of fumR results in silencing of the gene cluster and elimination of fumagillin biosynthesis. We found expression of fumR to also be dependent on laeA, a gene encoding another component of the fungal velvet complex. The results in this study argue that veA is a global regulator of secondary metabolism in A. fumigatus, and that veA may be a conduit via which chemical development is coupled to morphological development and other cellular processes.
Highlights
The filamentous fungus Aspergillus fumigatus is one of the most common human fungal pathogens found infecting a large population of immunodepressed patients
In a previous report we demonstrated that the global regulatory velvet gene veA controls A. fumigatus production of conidia [13], the main inoculum during infection [14,15], and production of gliotoxin [13], a compound with immunosuppressive properties [16,17,18,19,20,21,22,23,24,25,26,27,28] found to inhibit phagocytosis in macrophage and to induce apoptosis [29,30]
In 2003 our group described for the first time the role of veA as a global regulator of secondary metabolism in A. nidulans, including production of the mycotoxin sterigmatocystin [37]. veA regulates the biosynthesis of other mycotoxins, including aflatoxin, cyclopiazonic acid and aflatrem in Aspergillus flavus [33], the synthesis of trichothecenes in F. graminearum [38], and the production of fumonisins and PLOS ONE | www.plosone.org veA Is a Global Regulator in Aspergillus fumigatus fusarins in Fusarium spp, F. verticillioides and F. fujikuroi [32,39,40]
Summary
The filamentous fungus Aspergillus fumigatus is one of the most common human fungal pathogens found infecting a large population of immunodepressed patients This group includes individuals with hematological malignancies, those with genetic immunodeficiencies, patients infected with HIV, and cancer patients treated with chemotherapy [1,2,3,4,5,6]. VeA orthologs have been identified and characterized in other fungi [31,32] including other Aspergillus species, such as A. flavus [33,34,35], A. parasiticus [36] and the model filamentous fungus A. nidulans [37] These previous studies provided abundant evidence of the role of veA as a regulator of both fungal morphological development and secondary metabolism. VeA controls the synthesis of other secondary metabolites known for their beneficial medical applications, for example, the beta-lactam antibiotic penicillin in A. nidulans and P. chrysogenum [37,41] as well as cephalosporin C in Acremonium chrysogenum [42]
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