Bacillus subtilis Fur Is a Transcriptional Activator for the PerR-Repressed Gene, Encoding an Iron Efflux Pump.

The physiological relevance of bacterial iron efflux has only recently been appreciated. The P-type ATPase PfeT (eroxide-induced errous fflux ransporter) was one of the first iron efflux pumps to be characterized, and cells lacking accumulate high levels of intracellular iron. The promoter region has binding sites for both PerR, a peroxide-sensing Fur-family metalloregulator, and the ferric uptake repressor Fur. Both Fur and PerR bind DNA with Fe(II) as a cofactor. While reaction of PerR-Fe(II) with peroxide can account for the induction of under oxidative stress, binding of Fur-Fe(II) would be expected to lead to repression, which is inconsistent with the known role of PfeT as an iron efflux protein. Here, we show that expression of is repressed by PerR, as anticipated, and induced by Fur in response to Fe(II). Activation by Fur is mediated both by antagonism of the PerR repressor and by direct transcriptional activation, as confirmed using transcription assays. A similar mechanism of regulation can explain the iron induction of the PfeT ortholog and virulence factor, FrvA. Mutational studies support a model in which Fur activation involves regions both upstream and downstream of the promoter, and Fur and PerR have overlapping recognition of a shared regulatory element in this complex promoter region. This work demonstrates that Fur can function as an iron-dependent activator of transcription. Iron homeostasis plays a key role at the host-pathogen interface during the process of infection. Bacterial growth restriction resulting from host-imposed iron starvation (nutritional immunity) highlights the importance of iron import during pathogenesis. Conversely, bacterial iron efflux pumps function as virulence factors in several systems. The requirement for iron efflux in pathogens such as , , and suggests that both import and efflux are needed for cells to successfully navigate rapidly changing levels of iron availability in the host. Here, we provide insight into how iron efflux genes are controlled, an aspect of bacterial iron homeostasis relevant to infectious disease processes.