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.
Highlights
Aspergillus fumigatus is an opportunistic pathogen of immunosuppressed individuals
Supporting previous research data that indicates gliotoxin negatively impacts neutrophil migration [30] we found that supernatants of A. fumigatus OErsmA but not those of OErsmADgliZ or wild type inhibit human neutrophil chemotaxis
Our interest in exploring RsmA in impacting secondary metabolism in A. fumigatus arose from studies using the model genetic system, A. nidulans
Summary
Aspergillus fumigatus is an opportunistic pathogen of immunosuppressed individuals. Invasive aspergillosis (IA) represents a major cause of morbidity and mortality, with mortality rates ranging from 40% to 90% [1,2]. Part of the virulence of A. fumigatus is associated with its ability to produce a variety of toxic natural products. The functions of many fungal SMs remain to be determined, the known SMs of the genus Aspergillus have a tremendous impact on society. Compounds such as lovastatin (antihypercholesterolemic agent) and penicillin (antibiotic) are of clinical importance whereas the carcinogen, aflatoxin, causes both short term toxicities and long term liver cancer when humans eat contaminated crops [3]
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