The SrrAB two-component system regulates Staphylococcus aureus pathogenicity through redox sensitive cysteines

Abstract

Staphylococcus aureus infections can lead to diseases that range from localized skin abscess to life-threatening toxic shock syndrome. The SrrAB two-component system (TCS) is a global regulator of S. aureus virulence and critical for survival under environmental conditions such as hypoxic, oxidative, and nitrosative stress found at sites of infection. Despite the critical role of SrrAB in S. aureus pathogenicity, the mechanism by which the SrrAB TCS senses and responds to these environmental signals remains unknown. Bioinformatics analysis showed that the SrrB histidine kinase contains several domains, including an extracellular Cache domain and a cytoplasmic HAMP-PAS-DHp-CA region. Here, we show that the PAS domain regulates both kinase and phosphatase enzyme activity of SrrB and present the structure of the DHp-CA catalytic core. Importantly, this structure shows a unique intramolecular cysteine disulfide bond in the ATP-binding domain that significantly affects autophosphorylation kinetics. In vitro data show that the redox state of the disulfide bond affects S. aureus biofilm formation and toxic shock syndrome toxin-1 production. Moreover, with the use of the rabbit infective endocarditis model, we demonstrate that the disulfide bond is a critical regulatory element of SrrB function during S. aureus infection. Our data support a model whereby the disulfide bond and PAS domain of SrrB sense and respond to the cellular redox environment to regulate S. aureus survival and pathogenesis.

Quorum Sensing and Toxin Production in Staphylococcus aureus Osteomyelitis: Pathogenesis and Paradox

“…SrrB is a transmembrane histidine kinase that contains domains for dimerization, ATPase activity, and a phosphoacceptor [25]. The redox state of an intramolecular disulfide bond in the ATP-binding domain dictates the autophosphorylation state of SrrB [131]. SrrA is a cytoplasmic response regulator that can bind to DNA and influence transcriptional activity in a SrrB-dependent or -independent mechanism [25].…”

A Functional ClpXP Protease is Required for Induction of the Accessory Toxin Genes, tst, sed, and sec

“…The SrrAB (staphylococcal respiratory response) two-component-system was found to be a negative regulator of tst transcription [44]. Deletion of the srrAB genes, however, did not upregulate TSST-1 expression in the tst + model strain, MN8, indicating that tst transcription is not under strong negative regulation by the SrrAB system, under standard laboratory conditions [47]. Consistent with the latter finding, tst transcription was reduced in the RN4282clpX I265E cells, even though the expression of the srrAB operon was reduced 3-fold ( Table 1 and Table S1).…”

Thiol-based redox switches in the major pathogen Staphylococcus aureus

“…Reactive aldehydes might increase in S. aureus during the switch to biofilm formation and anaerobic fermentation, which relies on high glycolytic activity for ATP production. In the next section, we discuss the SrrAB system, which senses oxygen levels and controls the switch to anaerobiose and biofilm formation via the SrrB redox switch (Tiwari et al 2020;Yarwood and Schlievert 2000). Thus, GbaA and SrrAB might be responsible to sense different signals during biofilm formation and the switch from aerobic to anaerobic conditions to allow biofilm matrix synthesis, removal of toxic aldehydes and metabolic adaptation.…”

“…aureus utilizes SrrAB for adaptation to lower oxygen availability during anaerobiosis and changes in the respiratory flux (Yarwood and Schlievert 2000). SrrB senses the reduced state of the respiratory menaquinone pool and acts as kinase and phosphatase via the PAS domain to regulate the phosphorylation state of the response regulator SrrA (Kinkel et al 2013;Tiwari et al 2020). Two cysteines (Cys464 and Cys501) are present in the ATP-binding catalytic domain of SrrB, which are oxidized to an intramolecular disulfide under aerobic conditions inhibiting the autokinase activity of SrrB (Figure 11) (Tiwari et al 2020).…”

“…SrrB senses the reduced state of the respiratory menaquinone pool and acts as kinase and phosphatase via the PAS domain to regulate the phosphorylation state of the response regulator SrrA (Kinkel et al 2013;Tiwari et al 2020). Two cysteines (Cys464 and Cys501) are present in the ATP-binding catalytic domain of SrrB, which are oxidized to an intramolecular disulfide under aerobic conditions inhibiting the autokinase activity of SrrB (Figure 11) (Tiwari et al 2020). Under anaerobic conditions, the reduced menaquinone pool leads to reduction of the disulfide in SrrB, directly or indirectly via a PAS domain/ ligand complex, leading to a 40% increase in autophosphorylation of SrrB, which activates SrrA, affecting biofilm formation and tst toxin expression (Tiwari et al 2020).…”