Regulation of Iron Uptake by Fine-Tuning the Iron Responsiveness of the Iron Sensor Fur

Iron is one of most abundant environmental metal ions but is highly limited in organisms. It is an important metal ion as it facilitates various biological processes, including catalysis of metabolic enzymes and DNA biogenesis. In bacteria, the ferric uptake regulator (Fur) protein controls iron uptake by regulating genes coding for iron transporters in response to iron concentration. This iron response is ascribed to Fur's intrinsic affinity for iron because its binding to iron dictates its regulatory function. However, we now report that the pathogen Salmonella achieves a proper response of Fur to changes in environmental iron concentrations via EIIA^Ntr (a nitrogen metabolic phosphotransferase system component). We establish that EIIA^Ntr increases expression of iron transporter-coding genes under low-iron conditions (i.e., nanomolar ranges) in a Fur-dependent manner, which promotes Salmonella growth under such conditions. EIIA^Ntr directly hampers Fur binding to DNA, thereby inducing expression of those genes. This regulation allows Salmonella to express Fur-regulated genes under low-iron conditions. Our findings reveal a potentially widespread control mechanism of bacterial iron uptake systems operating in response to iron availability.IMPORTANCE Iron is a fundamental metal ion for living organisms as it facilitates various biological processes. The ferric uptake regulator (Fur) protein controls iron homeostasis in various bacterial species. It is believed that Fur's iron-dependent regulatory action is sufficient for it to function as an iron sensor. However, we now establish that the bacterial pathogen Salmonella enables Fur to properly reflect changes in surrounding iron availability by fine-tuning its responsiveness to iron. This process requires a protein that hampers Fur DNA binding at low iron concentrations. In this way, Salmonella broadens the range of iron concentrations that Fur responds to. Our findings reveal a potentially widespread control mechanism of bacterial iron homeostasis.