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.

doi:10.1073/pnas.1921307117

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

Journal Article · Thu Apr 30 00:00:00 EDT 2020 · Proceedings of the National Academy of Sciences of the United States of America

DOI:https://doi.org/10.1073/pnas.1921307117· OSTI ID:1642248

^[1]; López-Redondo, Marisa ^[2]; Miguel-Romero, Laura ^[2];

^[1]; Cahill, Michael P. ^[1];

^[1];

^[1]; Kilgore, Samuel H. ^[1]; Al-Tameemi, Hassan ^[3]; Herfst, Christine A. ^[4];

^[4]; Kirby, John R. ^[5];

^[3];

^[4]; Salgado-Pabón, Wilmara ^[1];

^[2]; Schlievert, Patrick M. ^[1]; Fuentes, Ernesto J. ^[1]

Univ. of Iowa, Iowa City, IA (United States)
Consejo Superior de Investigaciones Científicas (IBV-CSIC), Valencia (Spain); CIBER de Enfermedades Raras (CIBERER), Valencia (Spain)
Rutgers Univ., New Brunswick, NJ (United States)
Western Univ., London, ON (Canada)
Medical College of Wisconsin, Milwaukee, WI (United States)

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. In this work, 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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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: National Institutes of Health (NIH); USDA; Canadian Institutes of Health Research (CIHR); Ministerio de Economía y Competitividad (MINECO)

Grant/Contract Number:: AI135305; AI139100-01; AI134692-03; PJT-166050; BIO2016-78571-P

OSTI ID:: 1642248

Journal Information:: Proceedings of the National Academy of Sciences of the United States of America, Vol. 117, Issue 20; ISSN 0027-8424

Publisher:: National Academy of SciencesCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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Cited by: 42 works

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59 BASIC BIOLOGICAL SCIENCES
SrrAB two-component system
Staphylococcus aureus
sensor histidine kinase
cysteine disulfide bond

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

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