Nutritional regulation of the Sae two-component system by CodY in Staphylococcus aureus

Kevin D. Mlynek, William E. Sause, Derek E. Moormeier, Marat R. Sadykov, Kurt R. Hill, Victor J. Torres, Kenneth W. Bayles, Shaun R. Brinsmade

Research output: Contribution to journalArticlepeer-review

14 Scopus citations


Staphylococcus aureus subverts innate defenses during infection in part by killing host immune cells to exacerbate disease. This human pathogen intercepts host cues and activates a transcriptional response via the S. aureus exoprotein expression (SaeR/SaeS [SaeR/S]) two-component system to secrete virulence factors critical for pathogenesis. We recently showed that the transcriptional repressor CodY adjusts nuclease (nuc) gene expression via SaeR/S, but the mechanism remained unknown. Here, we identified two CodY binding motifs upstream of the sae P1 promoter, which suggested direct regulation by this global regulator. We show that CodY shares a binding site with the positive activator SaeR and that alleviating direct CodY repression at this site is sufficient to abrogate stochastic expression, suggesting that CodY represses sae expression by blocking SaeR binding. Epistasis experiments support a model that CodY also controls sae indirectly through Agr and Rot-mediated repression of the sae P1 promoter. We also demonstrate that CodY repression of sae restrains production of secreted cytotoxins that kill human neutrophils. We conclude that CodY plays a previously unrecognized role in controlling virulence gene expression via SaeR/S and suggest a mechanism by which CodY acts as a master regulator of pathogenesis by tying nutrient availability to virulence gene expression.

Original languageEnglish (US)
Article numbere00012-18
JournalJournal of bacteriology
Issue number8
StatePublished - Apr 1 2018


  • Branched-chain amino acids
  • CodY
  • Gene regulation
  • Sae
  • Sae TCS
  • Staphylococcus aureus
  • Two-component system
  • Virulence

ASJC Scopus subject areas

  • Microbiology
  • Molecular Biology


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