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 PmrA/PmrB two-component system of Salmonella enterica can be activated independently by Fe3+, which is sensed by the PmrB protein, and in low Mg2+, which is sensed by the PhoQ protein. The low-Mg2+ activation requires pmrD, a PhoP/PhoQ-activated gene that activates the response regulator PmrA at a posttranscriptional level. We now report that pmrD expression is negatively regulated by the PmrA/PmrB system. Conditions that activate the PmrA protein independently of pmrD, such as exposure to Fe3+, resulted in lower levels of pmrD transcription. The PmrA protein foot-printed 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 PhoP/PhoQ-activated pmrD gene by the PmrA/PmrB 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.