RsmA Regulates Aspergillus fumigatus Gliotoxin Cluster Metabolites Including Cyclo(L-Phe-L-Ser), a Potential New Diagnostic Marker for Invasive Aspergillosis

Abstract

Dimeric basic leucine zipper (bZIP) proteins are conserved transcriptional enhancers found in all eukaryotes. A recently reported and novel function for bZIPs is association of these proteins with secondary metabolite production in filamentous fungi. In particular a Yap-like bZIP termed RsmA (restorer of secondary metabolism A) was identified in Aspergillus nidulans that positively regulates the carcinogen sterigmatocystin. To assess for conserved function for RsmA, we examined a role of this protein in secondary metabolism in the pathogen A. fumigatus. RsmA was found to positively regulate gliotoxin where overexpression (OE) of rsmA led to 2-100 fold increases of twelve gli cluster metabolites in culture medium including the newly identified gli metabolite cyclo(L-Phe-L-Ser). Lungs from both wild type and OErsmA infected mice contained gliotoxin (2.3 fold higher in OErsmA treatment) as well as the gliotoxin precursor cyclo(L-Phe-L-Ser) (3.2 fold higher in OErsmA treatment). The data here presents a conserved role for RsmA in secondary metabolite cluster activation and suggests cyclo(L-Phe-L-Ser) may serve as an alternative marker for diagnosis of invasive aspergillosis.