The CorC proteins MgpA (YoaE) and CorC protect from excess-cation stress and are required for egg white tolerance and virulence in Salmonella

ABSTRACT Cation homeostasis is a vital function. In Salmonella, growth in very low Mg2+ induces expression of high-affinity Mg²⁺ transporters and 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 Mg2+ starvation. Deletion of corC causes a loss of viability additive with the paeA phenotype. Deletion of mgpA causes a synthetic defect in the corC background. This lethality is suppressed by loss of the inducible Mg2+ transporters, suggesting that the corC mgpA mutant is sensitive to changes in intracellular Mg2+. CorC and MgpA function independently of PaeA. A paeA mutant is sensitive to externally added polyamine in stationary phase; loss of CorC and MgpA suppressed this sensitivity. Conversely, the corC mgpA mutant, but not the paeA mutant, exhibited sensitivity to high Mg2+ 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 Mg2+ concentrations. Thus, CorC and MgpA play some interrelated role in cation homeostasis. It is unlikely that these phenotypes are due to absolute levels of cations. Rather, the cell maintains relative concentrations of various cations that likely compete for binding to anionic components. Imbalance of these cations affects some essential function(s), leading to a loss of viability. IMPORTANCE Mg²⁺ and other cations are critical for counteracting anionic compounds in the cell including RNA, DNA, and nucleotides. Both excessively low and 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. Competing Interest Statement The authors have declared no competing interest. Footnotes A file containing the Supplemental Data has been added.