RsmA regulates Aspergillus fumigatus gliotoxin cluster metabolites including cyclo(L-Phe-L-Ser), a potential new diagnostic marker for invasive aspergillosis

PLoS One. 2013 May 6;8(5):e62591. doi: 10.1371/journal.pone.0062591. Print 2013.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antifungal Agents / pharmacology
  • Aspergillus fumigatus / growth & development
  • Aspergillus fumigatus / metabolism*
  • Biomarkers / metabolism
  • Cell Movement
  • Cells, Cultured
  • Dipeptides / metabolism*
  • Drug Resistance, Fungal
  • Female
  • Fungal Proteins / genetics
  • Fungal Proteins / metabolism
  • Gene Expression Regulation, Fungal
  • Gliotoxin / metabolism*
  • Humans
  • Mice
  • Mice, Inbred ICR
  • Multigene Family
  • Neutrophils / physiology
  • Oxidative Stress
  • Peptides, Cyclic / metabolism*
  • Pulmonary Aspergillosis / diagnosis*
  • Pulmonary Aspergillosis / metabolism
  • Pulmonary Aspergillosis / microbiology
  • Up-Regulation
  • Vitamin K 3 / pharmacology


  • Antifungal Agents
  • Biomarkers
  • Dipeptides
  • Fungal Proteins
  • Peptides, Cyclic
  • phenylalanylserine
  • Gliotoxin
  • Vitamin K 3