title: 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.
authors.affiliation: Department of Bacteriology, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.
authors.forename: Relebohile
authors.initials: R
authors.lastname: Sekonyela
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Palmer
authors.forename: Jin-Woo
authors.initials: JW
authors.lastname: Bok
authors.forename: Sachin
authors.initials: S
authors.lastname: Jain
authors.forename: Erwin
authors.initials: E
authors.lastname: Berthier
authors.forename: Ry
authors.initials: R
authors.lastname: Forseth
authors.forename: Frank
authors.initials: F
authors.lastname: Schroeder
authors.forename: Nancy P
authors.initials: NP
authors.lastname: Keller
mesh_terms: D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology; D001232:Aspergillus fumigatus / Q000254:growth & development / Q000378:metabolism*; D015415:Biomarkers / Q000378:metabolism; D002465:Cell Movement; D002478:Cells, Cultured; D004151:Dipeptides / Q000378:metabolism*; D025141:Drug Resistance, Fungal; D005260:Female; D005656:Fungal Proteins / Q000235:genetics / Q000378:metabolism; D015966:Gene Expression Regulation, Fungal; D005912:Gliotoxin / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008813:Mice, Inbred ICR; D005810:Multigene Family; D009504:Neutrophils / Q000502:physiology; D018384:Oxidative Stress; D010456:Peptides, Cyclic / Q000378:metabolism*; D055732:Pulmonary Aspergillosis / Q000175:diagnosis* / Q000378:metabolism / Q000382:microbiology; D015854:Up-Regulation; D024483:Vitamin K 3 / Q000494:pharmacology
chemical_list: D000935:Antifungal Agents; D015415:Biomarkers; D004151:Dipeptides; D005656:Fungal Proteins; D010456:Peptides, Cyclic; C025275:phenylalanylserine; D005912:Gliotoxin; D024483:Vitamin K 3