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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.

The Fumagillin Gene Cluster, an Example of Hundreds of Genes under veA Control in Aspergillus fumigatus