Compartment and signal-specific codependence in the transcriptional control of Salmonella periplasmic copper homeostasis

Abstract

Copper homeostasis is essential for bacterial pathogen fitness and infection, and has been the focus of a number of recent studies. In Salmonella, envelope protection against copper overload and macrophage survival depends on CueP, a major copper-binding protein in the periplasm. This protein is also required to deliver the metal ion to the Cu/Zn superoxide dismutase SodCII. The Salmonella-specific CueP-coding gene was originally identified as part of the Cue regulon under the transcriptional control of the cytoplasmic copper sensor CueR, but its expression differs from the rest of CueR-regulated genes. Here we show that cueP expression is controlled by the concerted action of CueR, which detects the presence of copper in the cytoplasm, and by CpxR/CpxA, which monitors envelope stress. Copper-activated CueR is necessary for the appropriate spatial arrangement of the −10 and −35 elements of the cueP promoter, and CpxR is essential to recruit the RNA polymerase. The integration of two ancestral sensory systems—CueR, which provides signal specificity, and CpxR/CpxA, which detects stress in the bacterial envelope—restricts the expression of this periplasmic copper resistance protein solely to cells encountering surplus copper that disturbs envelope homeostasis, emulating the role of the CusR/CusS regulatory system present in other enteric bacteria.

The CpxR/CpxA system contributes to Salmonella gold‐resistance by controlling the GolS‐dependent gesABC transcription

“…). This was expected for a gene controlled by GolS (Checa et al ., ; Pontel et al ., ) because it requires the metal‐activated regulator to initiate transcription (Pezza et al ., ).…”

“…), suggesting that, besides GesABC pump, other factors under CpxR/CpxA‐control are involved in handling the stress caused by the toxic metal at the cell envelope. A similar effect has been previously reported when testing the sensitivity to copper, another group IB metal from the periodic table with similar physicochemical properties than Au, that severely impacts the cell envelope (Yamamoto and Ishihama, ; Pezza et al ., ).…”

“…CpxR is activated by conditions that disturb the cell envelope homeostasis and particularly the inner membrane, including alkaline pH, ethanol or metals such as Cu or Zn (Raivio, ; Delhaye et al ., ; Grabowicz and Silhavy, ; Pezza et al ., ; Surmann et al ., ). To verify the effective CpxR‐regulation of gesABC transcription, expression from a chromosomally encoded P ges‐lacZ reporter (Pontel et al ., ) was analyzed in the wild‐type strain as well as in mutants deleted in either cpxR or cpxA , or in both genes (Fig.…”

Contact killing and antimicrobial properties of copper

“…; Pezza et al . ). Abbreviations: MCO , multicopper oxidases; RND , resistance nodulation cell division.…”

“…It has been shown that CueP expression is controlled by a CueR‐like ‘activator‐type’ which can detect an increase in cytoplasmic concentration of copper using the two‐component system CpxR/CpxA when stress is detected at the bacterial membrane level (Pezza et al . ).…”