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

<jats:p> 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 <jats:italic>Salmonella enterica</jats:italic> can be activated independently by Fe <jats:sup>3+</jats:sup> , which is sensed by the PmrB protein, and in low Mg <jats:sup>2+</jats:sup> , which is sensed by the PhoQ protein. The low-Mg <jats:sup>2+</jats:sup> activation requires <jats:italic>pmrD</jats:italic> , a PhoP/PhoQ-activated gene that activates the response regulator PmrA at a posttranscriptional level. We now report that <jats:italic>pmrD</jats:italic> expression is negatively regulated by the PmrA/PmrB system. Conditions that activate the PmrA protein independently of <jats:italic>pmrD</jats:italic> , such as exposure to Fe <jats:sup>3+</jats:sup> , resulted in lower levels of <jats:italic>pmrD</jats:italic> transcription. The PmrA protein footprinted the <jats:italic>pmrD</jats:italic> 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 <jats:italic>pmrD</jats:italic> promoter abolished PmrA-mediated repression. Negative regulation of the PhoP/PhoQ-activated <jats:italic>pmrD</jats:italic> 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. </jats:p>