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

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 ZnZn2+ speciation changes induced by redox-driven depletion of soluble ZnZn2+ through formation of insoluble precipitates. In this way, CZBs utilize Zn2+ as a secondary messenger of exogenous redox potential, and correspondingly, cells exhibit chemoattraction toward Zn2+-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 Zn2+-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.