Iron plays a critical role in survival and virulence of the opportunistic pathogen Aspergillus fumigatus. Two
transcription factors, the
GATA-factor SreA and the bZip-factor HapX oppositely monitor
iron homeostasis with HapX activating
iron acquisition pathways (e.g.,
siderophores) and shutting down
iron consumptive pathways (and SreA) during
iron starvation conditions whereas SreA negatively regulates HapX and corresponding pathways during
iron sufficiency. Recently the non-ribosomal
peptide, hexadehydroastechrome (HAS; a
tryptophan-derived
iron (III)-complex), has been found important in A. fumigatus virulence. We found that HAS overproduction caused an
iron starvation phenotype, from alteration of
siderophore pools to regulation of
iron homeostasis gene expression including sreA. Moreover, we uncovered an
iron dependent secondary metabolism network where both SreA and HapX oppositely regulate multiple other secondary metabolites including HAS. This circuitry links
iron-acquisition and consumption pathways with secondary metabolism-thus placing HAS as part of a metabolic feedback circuitry designed to balance
iron pools in the fungus and presenting
iron availability as one environmental trigger of secondary metabolism.