The SrrAB two-component system regulates Staphylococcus aureus pathogenicity through redox sensitive cysteines. Proc Natl Acad Sci U S A 2020 May 19;117(20):10989-10999
Date
05/02/2020Pubmed ID
32354997Pubmed Central ID
PMC7245129DOI
10.1073/pnas.1921307117Scopus ID
2-s2.0-85084961758 (requires institutional sign-in at Scopus site) 50 CitationsAbstract
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 EJAuthor
John Kirby PhD Chair, Center Associate Director, Professor in the Microbiology and Immunology department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsBacterial 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
