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

doi:10.1073/pnas.0836837100

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

Department of Molecular Microbiology, Howard Hughes Medical Institute, Washington University School of Medicine, Campus Box 8230, 660 South Euclid Avenue, St. Louis, MO 63110

Edited by Roy Curtiss, Washington University, St. Louis, MO, and approved February 25, 2003 (received for review November 9, 2002)

Abstract

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 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 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.