Abstract
The acquisition of metal ions and the proper maturation of holo-metalloproteins are essential processes for all organisms. However, metal ion homeostasis is a double-edged sword. A cytosolic accumulation of metal ions can lead to mismetallation of proteins and cell death. Therefore, maintenance of proper concentrations of intracellular metals is essential for cell fitness and pathogenesis. Staphylococcus aureus, like all bacterial pathogens, uses transcriptional metalloregulatory proteins to aid in the detection and the genetic response to changes in metal ion concentrations. Herein, we review the mechanisms by which S. aureus senses and responds to alterations in the levels of cellular zinc, iron, heme, and copper. The interplay between metal ion sensing and metal-dependent expression of virulence factors is also discussed.
The Fe-responsive metalloregulator ferric uptake regulator (Fur) controls expression of virulence factors, including exoproteins, suggesting that the Staphylococcus aureus Fur-dependent regulon extends beyond genes utilized in Fe homeostasis.Fur and zinc uptake regulator (Zur) co-operate to regulate synthesis of staphylopine, a metallophore used to acquire metal ions by competing with host factors that provide nutritional immunity.The heme sensor system (HssRS) two-component regulatory system prevents heme intoxication by sensing cytosolic heme levels and increasing expression of HrtAB, which exports heme or heme metabolites.The Cu-responsive metalloregulator copper-sensitive operon regulator (CsoR) controls transcription of the copAZ Cu detoxification genes and the newly described copBL and copBmco operons that provide hypertolerance to Cu.The manganese transport regulator (MntR) metalloregulator preserves Mn homeostasis by regulating transcription of the Mn importer mntABC, as well as the expression of mntE to export excess cytosolic Mn.