Closing the loop: the PmrA/PmrB two-component system negatively controls expression of its posttranscriptional activator PmrD.

A fundamental question in biology is how an organism integrates multiple signals to mediate an appropriate cellular response. The PmrAPmrB two-component system of Salmonella enterica can be activated independently by Fe(3+), which is sensed by the PmrB protein, and in low Mg(2+), which is sensed by the PhoQ protein. The low-Mg(2+) activation requires pmrD, a PhoPPhoQ-activated gene that activates the response regulator PmrA at a posttranscriptional level. We now report that pmrD expression is negatively regulated by the PmrAPmrB system. Conditions that activate the PmrA protein independently of pmrD, such as exposure to Fe(3+), resulted in lower levels of pmrD transcription. The PmrA protein footprinted the pmrD promoter upstream of the PhoP-binding site but did not interfere with binding of the PhoP protein. Mutation of the PmrA-binding site in the pmrD promoter abolished PmrA-mediated repression. Negative regulation of the PhoPPhoQ-activated pmrD gene by the PmrAPmrB system closes a regulatory circuit designed to maintain proper cellular levels of activated PmrA protein and constitutes a singular example of a multicomponent feedback loop.