title: PTS phosphorylation of Mga modulates regulon expression and virulence in the group A streptococcus.
abstract: The ability of a bacterial pathogen to monitor available carbon sources in host tissues provides a clear fitness advantage. In the group A streptococcus (GAS), the virulence regulator Mga contains homology to phosphotransferase system (PTS) regulatory domains (PRDs) found in sugar operon regulators. Here we show that Mga was phosphorylated in vitro by the PTS components EI/HPr at conserved PRD histidines. A ΔptsI (EI-deficient) GAS mutant exhibited decreased Mga activity. However, PTS-mediated phosphorylation inhibited Mga-dependent transcription of emm in vitro. Using alanine (unphosphorylated) and aspartate (phosphomimetic) mutations of PRD histidines, we establish that a doubly phosphorylated PRD1 phosphomimetic (D/DMga4) is completely inactive in vivo, shutting down expression of the Mga regulon. Although D/DMga4 is still able to bind DNA in vitro, homo-multimerization of Mga is disrupted and the protein is unable to activate transcription. PTS-mediated regulation of Mga activity appears to be important for pathogenesis, as bacteria expressing either non-phosphorylated (A/A) or phosphomimetic (D/D) PRD1 Mga mutants were attenuated in a model of GAS invasive skin disease. Thus, PTS-mediated phosphorylation of Mga may allow the bacteria to modulate virulence gene expression in response to carbohydrate status. Furthermore, PRD-containing virulence regulators (PCVRs) appear to be widespread in Gram-positive pathogens.
authors: Department of Cell Biology & Molecular Genetics and Maryland Pathogen Research Institute, University of Maryland, College Park, MD 20742, USA.
authors: Elise R
authors: ER
authors: Hondorp
authors: Sherry C
authors: SC
authors: Hou
authors: Lara L
authors: LL
authors: Hause
authors: Kanika
authors: K
authors: Gera
authors: Ching-En
authors: CE
authors: Lee
authors: Kevin S
authors: KS
authors: McIver
mesh_terms: D000818:Animals; D001426:Bacterial Proteins / Q000378:metabolism*; D004269:DNA, Bacterial / Q000378:metabolism; D004195:Disease Models, Animal; D015964:Gene Expression Regulation, Bacterial; D051379:Mice; D010731:Phosphoenolpyruvate Sugar Phosphotransferase System / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding; D055503:Protein Multimerization; D018085:Regulon; D017192:Skin Diseases, Bacterial / Q000382:microbiology / Q000473:pathology; D013290:Streptococcal Infections / Q000382:microbiology / Q000473:pathology; D013297:Streptococcus pyogenes / Q000235:genetics* / Q000378:metabolism* / Q000472:pathogenicity; D014158:Transcription, Genetic; D014774:Virulence
chemical_list: D001426:Bacterial Proteins; D004269:DNA, Bacterial; C068267:mry protein, Streptococcus pyogenes; D010731:Phosphoenolpyruvate Sugar Phosphotransferase System
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