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Perturbation of manganese metabolism disrupts cell division in Streptococcus pneumoniae.

ABSTRACT: Manganese (Mn) is an essential micronutrient and required cofactor in bacteria. Despite its importance, excess Mn can impair bacterial growth, the mechanism of which remains largely unexplored. Here, we show that proper Mn homeostasis is critical for cellular growth of the major human respiratory pathogen Streptococcus pneumoniae. Perturbations in Mn homeostasis genes, psaBCA, encoding the Mn importer, and mntE, encoding the Mn exporter, lead to Mn sensitivity during aerobiosis. Mn-stressed cells accumulate iron and copper, in addition to Mn. Impaired growth is a direct result of Mn toxicity and does not result from iron-mediated Fenton chemistry, since cells remain sensitive to Mn during anaerobiosis or when hydrogen peroxide biogenesis is significantly reduced. Mn-stressed cells are significantly elongated, whereas Mn-limitation imposed by zinc addition leads to cell shortening. We show that Mn accumulation promotes aberrant dephosphorylation of cell division proteins via hyperactivation of the Mn-dependent protein phosphatase PhpP, a key enzyme involved in the regulation of cell division. We discuss a mechanism by which cellular Mn:Zn ratios dictate PhpP specific activity thereby regulating pneumococcal cell division. We propose that Mn-metalloenzymes are particularly susceptible to hyperactivation or mismetallation, suggesting the need for exquisite cellular control of Mn-dependent metabolic processes.

SUBMITTER: Martin JE

PROVIDER: S-EPMC5380469 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

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Perturbation of manganese metabolism disrupts cell division in Streptococcus pneumoniae.

Martin Julia E JE Lisher John P JP Winkler Malcolm E ME Giedroc David P DP

Molecular microbiology 20170221 2

Manganese (Mn) is an essential micronutrient and required cofactor in bacteria. Despite its importance, excess Mn can impair bacterial growth, the mechanism of which remains largely unexplored. Here, we show that proper Mn homeostasis is critical for cellular growth of the major human respiratory pathogen Streptococcus pneumoniae. Perturbations in Mn homeostasis genes, psaBCA, encoding the Mn importer, and mntE, encoding the Mn exporter, lead to Mn sensitivity during aerobiosis. Mn-stressed cell ...[more]

PMID: 28127804

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Project description:Streptococcus pneumoniae is an ovoid-shaped Gram-positive bacterium that grows by carrying out peripheral and septal peptidoglycan (PG) synthesis, analogous to model bacilli, such as Escherichia coli and Bacillus subtilis In the model bacilli, FtsZ and FtsA proteins assemble into a ring at midcell and are dedicated to septal PG synthesis but not peripheral PG synthesis; hence, inactivation of FtsZ or FtsA results in long filamentous cells unable to divide. Here, we demonstrate that FtsA and FtsZ colocalize at midcell in S. pneumoniae and that partial depletion of FtsA perturbs septum synthesis, resulting in elongated cells with multiple FtsZ rings that fail to complete septation. Unexpectedly, complete depletion of FtsA resulted in the delocalization of FtsZ rings and ultimately cell ballooning and lysis. In contrast, depletion or deletion of gpsB and sepF, which in B. subtilis are synthetically lethal with ftsA, resulted in enlarged and elongated cells with multiple FtsZ rings, with deletion of sepF mimicking partial depletion of FtsA. Notably, cell ballooning was not observed, consistent with later recruitment of these proteins to midcell after Z-ring assembly. The overproduction of FtsA stimulates septation and suppresses the cell division defects caused by the deletion of sepF and gpsB under some conditions, supporting the notion that FtsA shares overlapping functions with GpsB and SepF at later steps in the division process. Our results indicate that, in S. pneumoniae, both GpsB and SepF are involved in septal PG synthesis, whereas FtsA and FtsZ coordinate both peripheral and septal PG synthesis and are codependent for localization at midcell.IMPORTANCEStreptococcus pneumoniae (pneumococcus) is a clinically important human pathogen for which more therapies against unexploited essential targets, like cell growth and division proteins, are needed. Pneumococcus is an ovoid-shaped Gram-positive bacterium with cell growth and division properties that have important distinctions from those of rod-shaped bacteria. Gaining insights into these processes can thus provide valuable information to develop novel antimicrobials. Whereas rods use distinctly localized protein machines at different cellular locations to synthesize peripheral and septal peptidoglycans, we present evidence that S. pneumoniae organizes these two machines at a single location in the middle of dividing cells. Here, we focus on the properties of the actin-like protein FtsA as an essential orchestrator of peripheral and septal growth in this bacterium.

Project description:UnlabelledHow bacteria control proper septum placement at midcell, to guarantee the generation of identical daughter cells, is still largely unknown. Although different systems involved in the selection of the division site have been described in selected species, these do not appear to be widely conserved. Here, we report that LocZ (Spr0334), a newly identified cell division protein, is involved in proper septum placement in Streptococcus pneumoniae. We show that locZ is not essential but that its deletion results in cell division defects and shape deformation, causing cells to divide asymmetrically and generate unequally sized, occasionally anucleated, daughter cells. LocZ has a unique localization profile. It arrives early at midcell, before FtsZ and FtsA, and leaves the septum early, apparently moving along with the equatorial rings that mark the future division sites. Consistently, cells lacking LocZ also show misplacement of the Z-ring, suggesting that it could act as a positive regulator to determine septum placement. LocZ was identified as a substrate of the Ser/Thr protein kinase StkP, which regulates cell division in S. pneumoniae. Interestingly, homologues of LocZ are found only in streptococci, lactococci, and enterococci, indicating that this close phylogenetically related group of bacteria evolved a specific solution to spatially regulate cell division.ImportanceBacterial cell division is a highly ordered process regulated in time and space. Recently, we reported that the Ser/Thr protein kinase StkP regulates cell division in Streptococcus pneumoniae, through phosphorylation of several key proteins. Here, we characterized one of the StkP substrates, Spr0334, which we named LocZ. We show that LocZ is a new cell division protein important for proper septum placement and likely functions as a marker of the cell division site. Consistently, LocZ supports proper Z-ring positioning at midcell. LocZ is conserved only among streptococci, lactococci, and enterococci, which lack homologues of the Min and nucleoid occlusion effectors, indicating that these bacteria adapted a unique mechanism to find their middle, reflecting their specific shape and symmetry.

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Perturbation of manganese metabolism disrupts cell division in Streptococcus pneumoniae.

Publications

Perturbation of manganese metabolism disrupts cell division in Streptococcus pneumoniae.

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