Regulation of Bacterial Manganese Homeostasis and Usage During Stress Responses and Pathogenesis

Abstract

Manganese (Mn) plays a multifaceted role in the survival of pathogenic and symbiotic bacteria in eukaryotic hosts, and it is also important for free-living bacteria to grow in stressful environments. Previous research has uncovered components of the bacterial Mn homeostasis systems that control intracellular Mn levels, many of which are important for virulence. Multiple studies have also identified proteins that use Mn once it is inside the cell, including Mn-specific enzymes and enzymes transiently loaded with Mn for protection during oxidative stress. Emerging evidence continues to reveal proteins involved in maintaining Mn homeostasis, as well as enzymes that can bind Mn. For some of these enzymes, Mn serves as an essential cofactor. For other enzymes, mismetallation with Mn can lead to inactivation or poor activity. Some enzymes may even potentially be regulated by differential metallation with Mn or zinc (Zn). This review focuses on new developments in regulatory mechanisms that affect Mn homeostasis and usage, additional players in Mn import that increase bacterial survival during pathogenesis, and the interplay between Mn and other metals during Mn-responsive physiological processes. Lastly, we highlight lessons learned from fundamental research that are now being applied to bacterial interactions within larger microbial communities or eukaryotic hosts.

Filifactor alocis enhances survival of Porphyromonas gingivalis W83 in response to H2O2‐induced stress

“…During infection, manganese is an essential micronutrient for bacterial pathogens and has been shown to detoxify reactive oxygen species, either as a cofactor for manganese‐dependent catalases and superoxide dismutases or via its inherent ability to quench free radical‐mediated reactions (Fridovich, 1995; Tseng et al., 2001). Manganese homeostasis plays a major role in oxidative stress protection in an array of bacteria, including P. gingivalis (Akhtar & Turner, 2022; He et al., 2006; Martin & Waters, 2022). The ability of manganese ABC transporters to import manganese into the cytosol of pathogenic bacteria is indispensable for oxidative stress resistance.…”

The small protein MntS evolved from a signal peptide and acquired a novel function regulating manganese homeostasis in Escherichia coli

“…Since Mn is both required for cells and toxic in excess, its levels in cells must be carefully and dynamically controlled. Mn homeostasis and intracellular availability are regulated at many levels, including well‐studied transcriptional control of Mn transporters and newly recognized roles for RNA‐binding proteins, small RNAs, and protein stability of transporters (Martin & Waters, 2022). Here, we now report the role of a small protein, MntS, in regulating a Mn exporter.…”

“…Other bacteria require Mn for cellular differentiation and energy production (Gralnick & Newman, 2007; Jakubovics & Jenkinson, 2001; Kehres & Maguire, 2003; Vinyard et al., 2013). However, despite its beneficial functions, excess Mn can be toxic, likely by displacing other metals and rendering key proteins inactive (Bosma et al., 2021; Chandrangsu et al., 2017; Martin et al., 2015, 2017; Martin & Waters, 2022; Pi et al., 2020). Therefore, cells must monitor and respond rapidly to changing Mn levels to maintain optimal intracellular Mn concentrations.…”

“…Strains lacking Mn importers show sensitivity to ROS, metabolic limitations, and reduced virulence (Juttukonda & Skaar, 2015; Uppalapati & Vazquez‐Torres, 2022). At least five classes of dedicated Mn exporters are present across bacteria, loss of which causes sensitivity to high Mn via mismetallation of critical proteins and often also causes decreased virulence (Bosma et al., 2021; Martin et al., 2017; Martin & Waters, 2022; Waters, 2020). Escherichia coli possesses only the MntP exporter and MntH importer, as well as the more enigmatic Alx transporter, but lacks SitABCD (Bosma et al., 2021; Waters, 2020; Zeinert et al., 2018).…”

A nascent riboswitch helix orchestrates robust transcriptional regulation through signal integration

“…The yybP-ykoY RNA motif, known to sense manganese ions (Mn 2+ ), is a particularly widespread class of bacterial riboswitches that has been found in many human and plant pathogens, and regulates genes associated with Mn 2+ homeostasis through transcription or translation control 8 . It does so by selectively sensing Mn 2+ at sub-millimolar levels over the predominant, millimolar magnesium ion (Mg 2+ ) and any other divalents found in the cell 9,10 .…”