Staphylococcus aureus ZigA is implicated in survival in zinc-deplete and genotoxic environments

Zinc is a trace nutrient transition metal important to the host-microbe interface, as zinc is a cofactor for upwards of 10% of the pan-proteome. Given the importance of first-row transition metals, including zinc, to cellular life, it is predicted that Staphylococcus aureus and other pathogens have developed methods to distribute intracellular zinc across a hierarchy of protein clients. COG0523 proteins are a family of GTPase proteins present in all domains of life that act as post-translational regulators of client activity through direct protein-protein interactions. The pathogen S. aureus maintains three predicted COG0523 proteins, including ZigA. We confirm that S. aureus zigA is regulated by the zinc-responsive transcriptional regulator Zur. We further demonstrate that ZigA exhibits zinc-dependent GTPase activity and, in the presence of GTP, ZigA dimerizes. Co-immunoprecipitation and yeast-2-hybrid approaches resulted in a prioritized list of potential interacting partners for ZigA, including proteins involved in DNA repair, and in protection against oxidative stress. The loss of ZigA resulted in modest growth and survival defects when S. aureus experiences low zinc and DNA-damaging stresses, including UV crosslinking and reactive oxygen species. The loss of ZigA was not associated with phenotypes in the setting of other stressors, including iron limitation, antibiotic use, or stressors associated with COG0523 activity in other bacteria. During systemic infection, the loss of ZigA appears to only marginally impact S. aureus pathogenesis in the lung. Taken together, these data suggest that Zur-regulated ZigA may act as a dimer to support zinc-dependent, DNA damage repair by multiple mechanisms. IMPORTANCE In this work, Enriquez et al. study the response of Staphylococcus aureus to zinc limitation. Among these genes are those encoding the COG0523 proteins, which in bacteria and eukaryotes can act as metallochaperones. Zinc plays critical roles in S. aureus DNA damage repair machinery, which is particularly important during infection. This work proposes COG0523 protein ZigA as a minor contributor to staphylococcal pathogenesis in zinc-limited, genotoxic environments. Biochemical approaches suggest that ZigA dimerizes in the presence of GTP and that GTP activity is accelerated in the presence of zinc. Furthermore, the loss of ZigA results in modest S. aureus growth and survival defects associated with low-zinc and DNA-damaging environments. Taken together, these data suggest that Zur-regulated ZigA may act as a dimer to support zinc-dependent, DNA damage repair by multiple mechanisms.