Biology subjects

Franco, K.

Publications and source records attributed to Franco, K..

3 recordsLinked to original sources

bioRxiv2026

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 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.

microbiology↗

bioRxiv2026

Structure and signaling mechanism of Helicobacter pylori transducer-like protein D

Chemoreceptors, or methyl-accepting chemotaxis proteins (MCPs), are ancient and widespread prokaryotic sensors that direct taxis in response to stimuli and are attractive targets for therapeutic control of bacteria 1-4. Decades of study have yielded substantial mechanistic insight into chemoreceptor function, but the absence of high-resolution full-length structures containing ligand-binding domains (LBD) has limited understanding of how effector sensing is structurally coupled to long-range signal transduction. Here, we present the intact structure of the chemoreceptor transducer-like protein D (TlpD) from the gastric pathogen Helicobacter pylori, in complex with its ligand Zn2+, determined by X-ray crystallography in two crystal forms at 2.4-3.0 [A]. Three different conformations are captured, revealing how interactions in the ligand-binding site of the chemoreceptor zinc-binding (CZB) domain are interconnected with the distal kinase interface. Small changes at the ligand-binding site coincide with cascades of side-chain rearrangements across the dimer, distortion of the receptor coiled-coil, and conformational and dynamic shifts at the kinase interface over 140 [A] away. These near-atomic resolution structures provide a framework for understanding cooperativity and allosteric communication in chemoreceptors, and establish a representative model for a widespread class of soluble chemoreceptors important in bacterial pathogenesis 2,5.

molecular biology↗

bioRxiv2024

Navigating contradictions: Salmonella Typhimurium chemotactic responses to conflicting chemoeffector signals show parity with bacterial growth benefits

Motile bacteria sense and avoid deleterious stimuli in their environment through chemorepulsion, a behavior that helps them locate permissive ecological niches. In the gut, indole is a bacteriostatic compound produced by the microbiota and is thought to act as a chemorepellent for invading pathogens, thereby protecting the host against infection. The principal reservoir of intestinal indole is fecal matter, a complex biological material that contains both attractant and repellent stimuli. Whether indole in its natural context is sufficient for pathogen chemorepulsion or host protection has remained unknown. Using an intestinal explant system, we show that while pure indole indeed suppresses an infection advantage mediated through chemotaxis for the enteric pathogen Salmonella enterica serovar Typhimurium, this effect is abolished in the presence of other chemoeffectors present in feces, including the chemoattractant L-Serine (L-Ser), in a manner dependent on the chemoreceptor Tsr. Live imaging reveals that although S. Typhimurium is repelled by pure indole, the pathogen is actually strongly attracted to human fecal matter despite its high indole content, and that this response is mediated by Tsr, which simultaneously senses both indole and L-Ser. Fecal attraction is conserved across diverse Enterobacteriaceae species that harbor Tsr orthologues, including Escherichia coli, Citrobacter koseri, Enterobacter cloacae, and clinical isolates of non-typhoidal Salmonella. In a defined system of fecal chemoeffectors, we find that L-Ser and other fecal chemoattractants override indole chemorepulsion, but the magnitude of bacterial chemoattraction is controlled by indole levels. Together, these findings suggest that indole in its native context is not protective against enteric infection and that indole taxis actually benefits pathogens during infection by locating niches with low competitor density. Our study highlights the limitations of applying single-effector studies in predicting bacterial behavior in natural environments, where chemotaxis is shaped by the integration of multiple, often opposing, chemical signals.

microbiology↗