Perturbations in small molecule synthesis uncovers an iron-responsive secondary metabolite network in Aspergillus fumigatus.

Philipp Wiemann,Nancy P Keller,Liliana Losada,Joshua A Baccile,William C Nierman,Suman Pakala,Jin Woo Bok,Beatrix E Lechner,Thomas A Velk,Frank C Schroeder,Wen-Bing Yin,Hubertus Haas

doi:10.3389/fmicb.2014.00530

Abstract

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.

Highlights

The ubiquitous soil-dwelling filamentous fungus Aspergillus fumigatus can cause the life-threating disease invasive aspergillosis in immunocompromised individuals
HAS DOES NOT CONTRIBUTE TO SIDEROPHORE-ASSISTED IRON UPTAKE Since HAS was shown to chelate ferric iron, similar to the intraand extra-cellular siderophores produced by A. fumigatus, we investigated whether HAS could restore growth defects in an www.frontiersin.org
Confirming previous results (Schrettl et al, 2004a), sidA deletion mutants showed significant growth defects under iron depleted conditions compared to the wild type (WT), the hasA deletion mutant, the overexpression hasA mutant (OE::hasA), as well as a mutant overexpressing hasA in a hasD deletion background (OE::hasA/ hasD) where hasD encodes the non-ribosomal peptide synthetase required for HAS biosynthesis (Figure 1)

Summary

Introduction

The ubiquitous soil-dwelling filamentous fungus Aspergillus fumigatus can cause the life-threating disease invasive aspergillosis in immunocompromised individuals. Genes required for their production are generally clustered in fungal genomes, each gene in a specific cluster being subject to common regulatory patterns often triggered by largely unknown environmental cues (Hoffmeister and Keller, 2007; Brakhage, 2013). Some of these secondary metabolites have been shown to contribute to the fungus’ virulence (Jahn et al, 2002; Bok et al, 2006; Heinekamp et al, 2012; Berthier et al, 2013; Yin et al, 2013). Iron deficiency is known to serve as a regulatory cue for other virulence determinants in microorganisms (Litwin and Calderwood, 1993; Weinberg, 1999; Oglesby-Sherrouse et al, 2014) and has been shown to induce the production of the virulence factor ribotoxin AspF1 in A. fumigatus (Schrettl et al, 2010a)

Methods

Results

Conclusion