The SrrAB two-component system regulates Staphylococcus aureus pathogenicity through redox sensitive cysteines
- 30 April 2020
- journal article
- research article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences
- Vol. 117 (20), 10989-10999
- https://doi.org/10.1073/pnas.1921307117
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.Keywords
Funding Information
- HHS | NIH | National Institute of Allergy and Infectious Diseases (AI135305)
- HHS | NIH | National Institute of Allergy and Infectious Diseases (AI139100-01)
- HHS | NIH | National Institute of Allergy and Infectious Diseases (AI134692-03)
- Canadian Institutes of Health Research (PJT-166050)
- Ministerio de Economía y Competitividad (BIO2016-78751-P)
This publication has 75 references indexed in Scilit:
- Longitudinal genetic analyses of Staphylococcus aureus nasal carriage dynamics in a diverse populationBMC Infectious Diseases, 2013
- RegB Kinase Activity Is Repressed by Oxidative Formation of Cysteine Sulfenic AcidJournal of Biological Chemistry, 2013
- Methicillin-Susceptible Staphylococcus aureus Endocarditis Isolates Are Associated With Clonal Complex 30 Genotype and a Distinct Repertoire of Enterotoxins and AdhesinsThe Journal of Infectious Diseases, 2011
- Overview of theCCP4 suite and current developmentsActa Crystallographica Section D-Biological Crystallography, 2011
- The mechanism of signal transduction by two-component systemsCurrent Opinion in Structural Biology, 2010
- Kinetic Characterization of the WalRKSpn(VicRK) Two-Component System ofStreptococcus pneumoniae: Dependence of WalKSpn(VicK) Phosphatase Activity on Its PAS DomainJournal of Bacteriology, 2010
- α and β Chains of Hemoglobin Inhibit Production of Staphylococcus aureus ExotoxinsBiochemistry, 2007
- Coot: model-building tools for molecular graphicsActa Crystallographica Section D-Biological Crystallography, 2004
- Refinement of Macromolecular Structures by the Maximum-Likelihood MethodActa Crystallographica Section D-Biological Crystallography, 1997
- Basic Local Alignment Search ToolJournal of Molecular Biology, 1990