title: 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.
authors.affiliation: Department of Chemistry, Indiana University, Bloomington, IN, 47405-7102, USA.
authors.forename: Julia E
authors.initials: JE
authors.lastname: Martin
authors.affiliation: Department of Chemistry, Indiana University, Bloomington, IN, 47405-7102, USA.|Graduate Program in Biochemistry Indiana University, Bloomington, IN, 47405, USA.
authors.forename: John P
authors.initials: JP
authors.lastname: Lisher
authors.affiliation: Department of Biology, Indiana University, Bloomington, IN, 47405, USA.|Department of Molecular and Cellular Biochemistry, Indiana University, Bloomington, IN, 47405, USA.
authors.forename: Malcolm E
authors.identifier: 0000-0002-1482-2588
authors.initials: ME
authors.lastname: Winkler
authors.affiliation: Department of Chemistry, Indiana University, Bloomington, IN, 47405-7102, USA.|Department of Molecular and Cellular Biochemistry, Indiana University, Bloomington, IN, 47405, USA.
authors.forename: David P
authors.identifier: 0000-0002-2342-1620
authors.initials: DP
authors.lastname: Giedroc
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000378:metabolism / Q000502:physiology; D018829:Adhesins, Bacterial / Q000378:metabolism; D000332:Aerobiosis; D001426:Bacterial Proteins / Q000378:metabolism; D002455:Cell Division / Q000502:physiology; D003300:Copper / Q000378:metabolism; D015964:Gene Expression Regulation, Bacterial / Q000235:genetics; D006706:Homeostasis; D017136:Ion Transport / Q000502:physiology; D007501:Iron / Q000378:metabolism; D008345:Manganese / Q000378:metabolism* / Q000502:physiology; D018384:Oxidative Stress; D013296:Streptococcus pneumoniae / Q000235:genetics / Q000378:metabolism*; D014774:Virulence; D015032:Zinc / Q000378:metabolism
chemical_list: D018528:ATP-Binding Cassette Transporters; D018829:Adhesins, Bacterial; D001426:Bacterial Proteins; C115936:psaB protein, Streptococcus; D008345:Manganese; D003300:Copper; D007501:Iron; D015032:Zinc