Abstract
Cation homeostasis is a vital function. In Salmonella, growth in very low Mg(2+) induces expression of high-affinity Mg²(+) transporters and the synthesis of polyamines, organic cations that substitute for Mg²(+). Once Mg²(+) levels are re-established, the polyamines must be excreted by PaeA. Otherwise, cells lose viability due to a condition we term excess-cation stress. We sought additional tolerance mechanisms for this stress. We show that CorC and MgpA (YoaE) are essential for survival in stationary phase after Mg(2+) starvation. Deletion of corC causes a loss of viability that is additive with the paeA phenotype. Deletion of mgpA causes a synergistic defect in the corC background. This lethality is suppressed by the loss of the inducible Mg(2+) transporters, showing that the corC mgpA mutant is sensitive to changes in intracellular Mg(2+). CorC and MgpA function independently of PaeA. A paeA mutant is sensitive to externally added polyamine in stationary phase, while the loss of CorC and MgpA suppressed this sensitivity. Conversely, the corC mgpA mutant, but not the paeA mutant, exhibited sensitivity to high Mg(2+) and egg white. The corC mgpA mutant is also attenuated in a mouse model. The corC and mgpA genes are induced in response to increased Mg(2+) concentrations. Thus, CorC and MgpA have overlapping roles in cation homeostasis, most probably acting to efflux excess Mg(2+). Our data suggest that cells maintain relative concentrations of various cations that likely compete for binding to anionic components. The imbalance of these cations affects some essential function(s), leading to a loss of viability.IMPORTANCEMg²(+) and other cations are critical for counteracting anionic compounds in the cell including RNA, DNA, and nucleotides. Both excessively low and excessively high cation levels are toxic. To maintain proper intracellular concentrations, cells must regulate Mg²(+) importers and exporters or modulate the levels of other cations or anions that affect free Mg²(+) levels. In Salmonella, no mutants sensitive to high Mg²(+) levels have been identified. Here, we demonstrate that the largely uncharacterized proteins MgpA and CorC are induced under high Mg²(+) conditions and are essential for tolerance to high Mg²(+) levels. These genes are also essential for survival during endogenous excess-cation stress triggered by the transition to stationary phase after Mg²(+) starvation, as well as for virulence, highlighting the broader role of cation homeostasis.