COG0523 proteins act as bacterial and host determinants of Staphylococcus aureus growth and infection dynamics

Abstract

Heterogeneity associated with serious S. aureus infection occurs through multiple mechanisms by which bacteria circumvent host immunity and cause disease. Among these are mechanisms of trace nutrient transition metal, specifically of Zn2+ homeostasis, which informs the outcome of infection at the host -microbe interface. Emerging work has established the potential importance of COG0523 proteins in maintaining metal homeostasis at the host microbe interface (Critchlow, Rocchio, et al. 2025; Edmonds et al. 2021; Chandrangsu et al. 2019; Blaby-Haas et al. 2012; Haas et al. 2009). Further, S. aureus, M. musculus, and Homo sapiens encode one, if not multiple, Zn2+-binding COG0523 proteins (Weiss et al. 2022; Jordan et al. 2019).

COG0523 proteins are highly conserved members of the G3E P-loop GTPase family of proteins that contain metal-binding (CXCC) and Walker A and B NTPase domains (Edmonds et al. 2021; Haas et al. 2009). These domains enable the enzymatic activity of COG0523 sub-family members which have been characterized in bacteria and eukaryotes as transition metal dependent post-translational regulatory proteins (Capdevila et al. 2017; Chandrangsu et al. 2019; Jordan et al. 2019; Pasquini et al. 2022; Yang et al. 2015; Zhang, Braynen, et al. 2023; Weiss et al. 2022). COG0523 proteins have been demonstrated as metallochaperones of nickel, cobalt, and zinc ions, suggesting a conserved function of these metal-binding GTPases (Blaby-Haas et al. 2012; Chandrangsu et al. 2019; Haas et al. 2009; Sydor et al. 2013; Yang et al. 2018; Yang et al. 2015; Weiss et al. 2022). Collectively, this dissertation is focused on defining the contribution of host and S. aureus COG0523 proteins to the host-microbe interface. In Chapter II these investigations begin with determining the potential function of S. aureus COG0523 protein ZigA, and the contribution of ZigA to staphylococcal growth and survival in the setting of Zn2+ limitation. In Chapter III, the study of COG0523 proteins switches from S. aureus to small animal model hosts, where host COG0523 protein ZNG1 is known to contribute to host proteostasis. The goal of this chapter is two-fold; to determine the impact of ZNG1 on S. aureus systemic infection, specifically in the kidney, and to test they hypothesis that ZNG1 has roles outside of METAP-metallostasis.