Regulation of iron ion homeostasis in <i>Staphylococcus aureus</i> and its impact on physiology and virulence

ABSTRACT Bacteria use transcription factors and small regulatory RNAs as modulators of transcription and translation to respond effectively to diverse environmental and internal stressors. Nearly all bacteria require iron (Fe), and in host niches, pathogenic bacteria encounter a shortage of available Fe ions; their response to Fe depletion significantly affects their physiology and pathogenesis. Here, we review how the bacterial pathogen Staphylococcus aureus uses the ferric uptake regulator (Fur), Fur protein antagonist (Fpa), AcnA, and iron-sparing response regulator (IsrR) to regulate gene expression in response to changes in cytosolic Fe levels. Fur is a transcription factor that uses Fpa and Fe(II) ions to regulate the transcription of genes, including those involved in Fe uptake. Upon Fe limitation,Fpa mediates alleviation of Fur repression. This enables the expression of the IsrR, a non-coding RNA. IsrR binds to and represses translation of mRNAs encoding proteins that require Fe or are involved in Fe-dependent processes, thereby mediating an Fe-sparing response. In response to Fe depletion, Fur and IsrR promote increased Fe uptake and a general shift toward fermentative metabolism for energy conservation. IsrR also directly mediates the translational repression of detoxification mechanisms against oxidative stress and directly or indirectly alters the expression of virulence factors. Fe depletion also impacts the iron-sulfur enzyme aconitase by enriching for the apo-form, which moonlights as an RNA-binding protein (RBP) with regulatory activity. We showcase how transcription factors, non-coding RNAs, and RBPs control bacterial Fe homeostasis, highlighting their roles as critical mediators of bacterial stress responses and virulence.