Bacterial manganese sensing and homeostasis
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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2023, International Journal of Biological MacromoleculesIron-responsive riboswitches
2022, Current Opinion in Chemical BiologyCitation Excerpt :Notably, in vitro, millimolar concentrations of MnII, CaII, SrII, and CoII can also induce a similar conformational change; in vivo, MgII selectivity is maintained because the riboswitch rarely, if ever, encounters such high concentrations of these other metals [17]. MnII-responsive riboswitches [18–20] regulating manganese exporters have also been identified [2,21]. Another riboswitch family, regulating putative heavy metal transporters (including czcD genes), was characterized in 2015 as being most responsive to CoII and NiII based on in vitro and limited in-cell studies; therefore, the riboswitch was dubbed “NiCo” (Figure 1b) [22].
Primary nutrient sensors in plants
2022, iScienceCitation Excerpt :Information about sensing of these nutrients (Mn and Ni) comes primarily from work on bacteria. For example, Mn sensors in bacteria have been characterized and may involve both protein type sensors (i.e. transcription factors that bind Mn) and RNA-based sensors (riboswitches) that regulate the expression of Mn transporters (Waters, 2020). These sensors regulate Mn uptake systems such as ABC and NRAMP transporters.