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

Tiwari, Nitija, López-Redondo, Marisa, Miguel-Romero, Laura, Kulhankova, Katarina, Cahill, Michael P., Tran, Phuong M., Kinney, Kyle J., Kilgore, Samuel H., Al-Tameemi, Hassan, Herfst, Christine A., Tuffs, Stephen W., Kirby, John R., Boyd, Jeffery M., McCormick, John K., Salgado-Pabón, Wilmara, Marina, Alberto, Schlievert, Patrick M., Fuentes, Ernesto J.·2020·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.1921307117
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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.

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Metadata

Authors
Tiwari, N., López-Redondo, M., Miguel-Romero, L., Kulhankova, K., Cahill, M. P., Tran, P. M., Kinney, K. J., Kilgore, S. H., Al-Tameemi, H., Herfst, C. A., Tuffs, S. W., Kirby, J. R., Boyd, J. M., McCormick, J. K., Salgado-Pabón, W., Marina, A., Schlievert, P. M., & Fuentes, E. J.
Affiliations
  • Department of Biochemistry, University of Iowa, Iowa City, IA 52242;
  • Instituto de Biomedicina de Valencia, Consejo Superior de Investigaciones Científicas (IBV-CSIC), 46010 Valencia, Spain;
  • Department of Microbiology and Immunology, University of Iowa, Iowa City, IA 52242;
  • Department of Biochemistry and Microbiology, Rutgers University, New Brunswick, NJ 08901-8525;
  • Department of Microbiology and Immunology, Western University, London, ON N6A 5C1, Canada;
  • Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, WI 53226
ORCID
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
2020-04-30
Volume
117
Issue
20
Pages
10989-10999
ISSN
  • 0027-8424
  • 1091-6490
DOI
10.1073/pnas.1921307117
Cited by
88
References
0
Language
en
Licence
www.pnas.org/site/aboutpnas/licenses.xhtml (vor, 183 d)
Funders
  • HHS | NIH | National Institute of Allergy and Infectious Diseases (AI135305, AI139100-01, AI134692-03)
  • Canadian Institutes of Health Research (PJT-166050)
  • Ministerio de Economía y Competitividad (BIO2016-78751-P)

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Tiwari, N., López-Redondo, M., Miguel-Romero, L., Kulhankova, K., Cahill, M. P., Tran, P. M., Kinney, K. J., Kilgore, S. H., Al-Tameemi, H., Herfst, C. A., Tuffs, S. W., Kirby, J. R., Boyd, J. M., McCormick, J. K., Salgado-Pabón, W., Marina, A., Schlievert, P. M., & Fuentes, E. J. (2020). The SrrAB two-component system regulates Staphylococcus aureus pathogenicity through redox sensitive cysteines. Proceedings of the National Academy of Sciences. https://doi.org/10.1073/pnas.1921307117

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