Identification of a U/Zn/Cu responsive global regulatory two‐component system in Caulobacter crescentus

Summary Despite the well‐known toxicity of uranium (U) to bacteria, little is known about how cells sense and respond to U. The recent finding of a U‐specific stress response in Caulobacter crescentus has provided a foundation for studying the mechanisms of U‐ perception in bacteria. To gain insight into this process, we used a forward genetic screen to identify the regulatory components governing expression of the urcA promoter (P urcA ) that is strongly induced by U. This approach unearthed a previously uncharacterized two‐component system, named UzcRS, which is responsible for U‐dependent activation of P urcA . UzcRS is also highly responsive to zinc and copper, revealing a broader specificity than previously thought. Using ChIP‐seq, we found that UzcR binds extensively throughout the genome in a metal‐dependent manner and recognizes a noncanonical DNA‐binding site. Coupling the genome‐wide occupancy data with RNA‐seq analysis revealed that UzcR is a global regulator of transcription, predominately activating genes encoding proteins that are localized to the cell envelope; these include metallopeptidases, multidrug‐resistant efflux (MDR) pumps, TonB‐dependent receptors and many proteins of unknown function. Collectively, our data suggest that UzcRS couples the perception of U, Zn and Cu with a novel extracytoplasmic stress response.