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PTS phosphorylation of Mga modulates regulon expression and virulence in the group A streptococcus

Elise R Hondorp1, Sherry C Hou, Lara L Hause

  • 1Department of Cell Biology & Molecular Genetics and Maryland Pathogen Research Institute, University of Maryland, College Park, MD 20742, USA.

Molecular Microbiology
|May 9, 2013
PubMed

Insights

Group A Streptococcus uses the phosphotransferase system (PTS) to phosphorylate the Mga virulence regulator, controlling gene expression. This PTS-mediated phosphorylation impacts bacterial pathogenesis and virulence in host tissues.

Area of Science:

  • Microbiology
  • Bacterial Pathogenesis
  • Molecular Biology

Background:

  • Bacterial pathogens utilize nutrient sensing for host adaptation.
  • The Group A Streptococcus (GAS) virulence regulator Mga shares homology with phosphotransferase system (PTS) regulatory domains (PRDs).

Purpose of the Study:

  • To investigate the role of PTS-mediated phosphorylation in regulating GAS Mga activity.
  • To determine the impact of Mga phosphorylation on GAS virulence and pathogenesis.

Main Methods:

  • In vitro phosphorylation assays using purified PTS components (EI/HPr) and Mga.
  • Construction and characterization of GAS mutants with altered Mga phosphorylation sites (alanine and aspartate substitutions).
  • Assessment of Mga activity, DNA binding, homo-multimerization, and transcriptional activation in vitro and in vivo.
  • Evaluation of bacterial attenuation in a mouse model of invasive skin disease.

Main Results:

  • Mga is phosphorylated by EI/HPr at conserved PRD histidines.
  • PTS-mediated phosphorylation inhibits Mga-dependent transcription of emm.
  • A phosphomimetic Mga mutant (D/DMga4) is inactive in vivo, disrupting Mga regulon expression.
  • Non-phosphorylated and phosphomimetic Mga mutants show attenuated virulence in a GAS skin infection model.
  • Homo-multimerization of Mga is disrupted upon phosphorylation, preventing transcriptional activation.

Conclusions:

  • PTS-mediated phosphorylation of Mga is a key mechanism for modulating GAS virulence gene expression in response to carbohydrate availability.
  • This regulatory pathway is crucial for GAS pathogenesis.
  • PRD-containing virulence regulators (PCVRs) are likely prevalent in Gram-positive pathogens.

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