Perturbation of manganese metabolism disrupts cell division in Streptococcus pneumoniae

Mol Microbiol. 2017 Apr;104(2):334-348. doi: 10.1111/mmi.13630. Epub 2017 Feb 21.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • ATP-Binding Cassette Transporters / metabolism
  • ATP-Binding Cassette Transporters / physiology
  • Adhesins, Bacterial / metabolism
  • Aerobiosis
  • Bacterial Proteins / metabolism
  • Cell Division / physiology
  • Copper / metabolism
  • Gene Expression Regulation, Bacterial / genetics
  • Homeostasis
  • Ion Transport / physiology
  • Iron / metabolism
  • Manganese / metabolism*
  • Manganese / physiology
  • Oxidative Stress
  • Streptococcus pneumoniae / genetics
  • Streptococcus pneumoniae / metabolism*
  • Virulence
  • Zinc / metabolism

Substances

  • ATP-Binding Cassette Transporters
  • Adhesins, Bacterial
  • Bacterial Proteins
  • psaB protein, Streptococcus
  • Manganese
  • Copper
  • Iron
  • Zinc