SRE1 Regulates Iron-Dependent and -Independent Pathways in the Fungal Pathogen Histoplasma capsulatum

Abstract

Regulation of iron acquisition genes is critical for microbial survival under both iron-limiting conditions (to acquire essential iron) and iron-replete conditions (to limit iron toxicity). In fungi, iron acquisition genes are repressed under iron-replete conditions by a conserved GATA transcriptional regulator. Here we investigate the role of this transcription factor, Sre1, in the cellular responses of the fungal pathogen Histoplasma capsulatum to iron. We showed that cells in which SRE1 levels were diminished by RNA interference were unable to repress siderophore biosynthesis and utilization genes in the presence of abundant iron and thus produced siderophores even under iron-replete conditions. Mutation of a GATA-containing consensus site found in the promoters of these genes also resulted in inappropriate gene expression under iron-replete conditions. Microarray analysis comparing control and SRE1-depleted strains under conditions of iron limitation or abundance revealed both ironresponsive genes and Sre1-dependent genes, which comprised distinct but overlapping sets. Iron-responsive genes included those encoding putative oxidoreductases, metabolic and mitochondrial enzymes, superoxide dismutase, and nitrosative-stressresponse genes; Sre1-dependent genes were of diverse functions. Genes regulated by iron levels and Sre1 included all of the siderophore biosynthesis genes, a gene involved in reductive iron acquisition, an iron-responsive transcription factor, and two catalases. Based on transcriptional profiling and phenotypic analyses, we conclude that Sre1 plays a critical role in the regulation of both traditional iron-responsive genes and iron-independent pathways such as regulation of cell morphology. These data highlight the evolving realization that the effect of Sre1 orthologs on fungal biology extends beyond the iron regulon.

Intracellular siderophore but not extracellular siderophore is required for full virulence in Metarhizium robertsii

“…Overall regulation of mrsidC, mrsidD and mrsreA as well as the effect of disruption of mrsreA on expression of mrsidD is very similar to what has been observed in other fungi (Hwang et al, 2012;Oberegger et al, 2001;Schrettl et al, 2008). However, the same studies indicated that the range of the genes affected by mrsreA orthologs is species-specific and may include virulence factors beyond iron acquisition.…”

The Monothiol Glutaredoxin Grx4 Exerts an Iron-Dependent Inhibitory Effect on Php4 Function

“…In contrast, when iron levels are low, Fep1 is unable to bind chromatin, which results in transcriptional activation of iron transport genes (18). Iron-dependent regulators possessing similar functions and sequences to Fep1 have been identified in several fungi, but not in Saccharomyces cerevisiae (2,6,7,9,15,20). Recent studies have shown that the monothiol glutaredoxin Grx4 is a binding partner of Fep1 and that it plays a critical role in inhibiting Fep1 function when cells undergo a transition from iron-sufficient to iron-limiting conditions (17,23).…”

Redundant Catalases Detoxify Phagocyte Reactive Oxygen and Facilitate Histoplasma capsulatum Pathogenesis

“…Consistent with this, exogenous peroxide does not upregulate CatB and CatP expression (28). The only evidence for Histoplasma CatB regulation is increased CATB expression when iron concentrations increase, presumably to prevent the formation of hydroxyl radicals by destroying the predecessor molecule, hydrogen peroxide (78).…”