Oxygen sensing and redox signaling significantly affect bacterial physiology and host-pathogen interaction. Here we show that a Staphylococcus aureus two-component system, AirSR (anaerobic iron-sulfur cluster-containing redox sensor regulator, formerly YhcSR), responds to oxidation signals (O 2, H 2O 2, NO, etc) by using a redox-active [2Fe-2S] cluster in the sensor kinase AirS. Mutagenesis studies demonstrate that the [2Fe-2S] cluster is essential for the kinase activity of AirS. We have also discovered that a homologue of IscS (SA1450) in S. aureus is active as a cysteine desulfurase, which enables the in vitro reconstitution of the [2Fe-2S] cluster in AirS. Phosphorylation assays show that the oxidized AirS with a [2Fe-2S] 2+ cluster is the fully active form of the kinase but not the apo-AirS nor the reduced AirS possessing a [2Fe-2S] + cluster. Overoxidation by prolonged exposure to O 2 or contact with H 2O 2 or NO led to inactivation of AirS. Transcriptome analysis revealed that mutation of airR impacts the expression of ∼355 genes under anaerobic conditions. Moreover, the mutant strain displayed increased resistance toward H 2O 2, vancomycin, norfloxacin, and ciprofloxacin under anaerobic conditions. Together, our results show that S. aureus AirSR is a redox-dependent global regulatory system that plays important roles in gene regulation using a redox active Fe-S cluster under O 2-limited conditions.
ASJC Scopus subject areas
- Colloid and Surface Chemistry