Zn2+ as a secondary messenger for exogenous redox potential sensed through Chemosensory Zinc-Binding (CZB) protein domains

Abstract

Redox environments in nature are shaped by reactive oxygen species (ROS), oxygen availability, and metal ion chemistry, and exert profound effects on cell physiology and survival. While extensive work has characterized how cells resist oxidative damage, the mechanisms by which cells sense and navigate environmental redox conditions remain less well understood. Here, we identify a previously unrecognized and widespread mechanism of redox sensing in Salmonella enterica serovar Typhimurium mediated by the chemosensory zinc-binding (CZB) domain-containing receptor McpA. Using quantitative chemotaxis assays and live-cell imaging, we show that S. Typhimurium exhibits robust, concentration-dependent chemotaxis toward the neutrophil-derived oxidants HOCl and hydroperoxides, with attraction occurring at low, physiologically relevant concentrations below those that cause bactericidal effects, and this response requires McpA and its conserved zinc-binding cysteine. Whereas other Cys-Zn thiolate systems function through direct oxidation mechanisms, we find that the unique 3His,1Cys binding motif of CZBs responds to redox-dependent changes in Zn{superscript 2} speciation, whereby oxidizing conditions shift soluble, bioavailable Zn{superscript 2} into insoluble zinc precipitates. In this way, CZBs utilize the bioavailable Zn{superscript 2} pool as a secondary messenger of exogenous redox potential, and correspondingly, cells exhibit chemoattraction toward Zn{superscript 2}-depleted environments, including sources of ROS, but also toward oxygen-rich conditions that provide a metabolic growth advantage. The broad phylogenetic distribution of CZB domains is consistent with this Zn{superscript 2}-responsive mechanism being an ancient redox-sensing strategy, likely established early in bacterial evolution under changing planetary redox conditions and retained across diverse bacterial lineages. Significance StatementWe report a previously unknown mechanism of redox sensing that operates through changes in the bioavailability and speciation of Zn{superscript 2}, enabling bacteria to detect changes in exogenous redox potential with high sensitivity and navigate redox gradients. The broad phylogenetic distribution of chemosensory zinc-binding (CZB) domains suggests that this zinc-dependent sensory mechanism is an ancient and widespread strategy for detecting environmental redox gradients that arose early in bacterial evolution and may have been subsequently shaped or expanded in response to increasing atmospheric oxygen associated with the Great Oxygenation Event.