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The SrrAB two-component system regulates Staphylococcus aureus pathogenicity through redox sensitive cysteines. Proc Natl Acad Sci U S A 2020 05 19;117(20):10989-10999

Date

05/02/2020

Pubmed ID

32354997

Pubmed Central ID

PMC7245129

DOI

10.1073/pnas.1921307117

Scopus ID

2-s2.0-85084961758   6 Citations

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.

Author List

Tiwari N, López-Redondo M, Miguel-Romero L, Kulhankova K, Cahill MP, Tran PM, Kinney KJ, Kilgore SH, Al-Tameemi H, Herfst CA, Tuffs SW, Kirby JR, Boyd JM, McCormick JK, Salgado-Pabón W, Marina A, Schlievert PM, Fuentes EJ

Author

John Kirby PhD Chair, Center Associate Director, Professor in the Microbiology and Immunology department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Animals
Bacterial Proteins
Bacterial Toxins
Base Sequence
Biofilms
Catalytic Domain
Cysteine
Disease Models, Animal
Endocarditis
Enterotoxins
Female
Gene Expression Regulation, Bacterial
Histidine Kinase
Male
Models, Molecular
Mutation
Oxidation-Reduction
Protein Domains
Rabbits
Repressor Proteins
Sepsis
Staphylococcal Infections
Staphylococcus aureus
Superantigens
Thermotoga maritima
Virulence