Bacterial manganese sensing and homeostasis

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Manganese (Mn) plays a complex role in the survival of pathogenic and symbiotic bacteria in eukaryotic hosts and is also important for free-living bacteria to thrive in stressful environments. This review summarizes new aspects of regulatory strategies to control intracellular Mn levels and gives an overview of several newly identified families of bacterial Mn transporters. Recent illustrative examples of advances in quantification of intracellular Mn pools and characterization of the effects of Mn perturbations are highlighted. These discoveries help define mechanisms of Mn selectivity and toxicity and could enable new strategies to combat pathogenic bacteria and promote growth of desirable bacteria.

Introduction

Transition metals (manganese (Mn), iron (Fe), cobalt (Co), nickel (Ni), copper (Cu), and zinc (Zn)) are essential nutrients for bacteria, yet these metals can also be toxic in excess. The mammalian immune system takes advantage of this vulnerability and withholds critical metals, including Mn, Fe, and Zn, to starve invading bacteria in a process termed nutritional immunity [1, 2, 3]. In other situations, host defenses intoxicate bacteria with high concentrations of metals, notably Cu and Zn but also possibly Mn and Fe, during colonization of eukaryotic hosts [3, 4, ∗∗5].

Mn is required for the proper growth of many bacteria. Molecularly, Mn cofactors diverse enzymes involved in carbohydrate and nucleic acid metabolism, signaling, and oxidative stress resistance [6,7]. Mn also protects cells against oxidative stress, primarily by breaking down reactive oxygen species (ROS) (Box 1) [2,8]. However, despite these beneficial roles, excess Mn perturbs intracellular pools of other ions and causes mismetallation of important regulators and enzymes, sensitivity to ROS, and decreased virulence [5].

Therefore, to maintain an optimal Mn concentration, bacteria control intracellular Mn levels with Mn importers and exporters (Figure 1). Expression of these transporters is regulated by Mn-sensing transcription factors and riboswitches. Once inside the cell, Mn associates with various molecules, including proteins, nucleic acids, and small metabolites, in different intracellular pools [5].

This article summarizes recent findings regarding how Mn-binding regulators control gene expression, characterization of new classes of Mn exporters, the speciation and availability of intracellular Mn pools, and molecular mechanisms of Mn toxicity. Specifically, I review recent studies of (a) Mn regulators, including MntR oligomerization and the metal selectivity of the Mn-binding yybP-ykoY riboswitch; (b) newly identified Mn exporters; and (c) quantification and perturbation of intracellular Mn pools.

Section snippets

Regulators: Mn-binding transcription factors and riboswitches

Bacteria have two main mechanisms to regulate the expression of genes encoding Mn homeostasis proteins: Mn-binding transcription factors and a Mn-binding riboswitch (Figure 1).

The major transcriptional regulator controlling bacterial Mn homeostasis is the DtxR family protein, MntR [2,5]. In the absence of metal binding, the MntR apoprotein is found as a dimer in solution. Mn binding to MntR causes an allosteric change that allows it to bind DNA. Although noncognate metals bind MntR in vitro,

New families of Mn exporters

While the major classes of bacterial Mn importers have been known for some time [2,7], new families of Mn exporters are still emerging (Figure 1). The first discovered Mn exporter, the cation diffuser family (CDF) protein MntE, was identified a decade ago in S. pneumoniae [20]. Intriguingly, despite the observation that many pathogenic bacteria require Mn during infection and the fact that MntE reduces intracellular Mn levels, loss of MntE was shown to decrease virulence [20]. Subsequent

Quantification of intracellular Mn pools and metal selectivity

Regulated expression of importers and exporters controls the total intracellular levels of metals, called the quota. Importantly, however, metals are partitioned into different pools once inside of the cell (Figure 1, Box 2). Methods to robustly measure these different Mn populations have been challenging to develop. Two main approaches used to quantify available metal pools have been electron paramagnetic resonance (EPR) spectroscopy and thermodynamic models to determine the sensitivities of

Perspective

In summary, significant progress has been made in understanding how Mn transporters and Mn-binding regulatory factors work, including recent work on Mn-dependent gene regulation, identifying new Mn homeostasis proteins, and characterizing Mn pools in cells. But by analogy with other metal homeostasis systems, dedicated factors that sequester excess Mn or that mobilize intracellular stores during Mn deficiency may also exist. Possible candidates include the MntR-regulated Dps protein and other

Conflict of interest statement

Nothing declared.

Acknowledgements

The author wishes to acknowledge Julia Martin for critical discussion of this manuscript. Work in the Waters laboratory is supported by the University of Wisconsin Oshkosh Faculty Development program and Research Corporation for Science Advancement (Cottrell Scholars Award 23595 to LSW).

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