title: Quorum-sensing agr mediates bacterial oxidation response via an intramolecular disulfide redox switch in the response regulator AgrA.
abstract: Oxidation sensing and quorum sensing significantly affect bacterial physiology and host-pathogen interactions. However, little attention has been paid to the cross-talk between these two seemingly orthogonal signaling pathways. Here we show that the quorum-sensing agr system has a built-in oxidation-sensing mechanism through an intramolecular disulfide switch possessed by the DNA-binding domain of the response regulator AgrA. Biochemical and mass spectrometric analysis revealed that oxidation induces the intracellular disulfide bond formation between Cys-199 and Cys-228, thus leading to dissociation of AgrA from DNA. Molecular dynamics (MD) simulations suggest that the disulfide bond formation generates a steric clash responsible for the abolished DNA binding of the oxidized AgrA. Mutagenesis studies further established that Cys-199 is crucial for oxidation sensing. The oxidation-sensing role of Cys-199 is further supported by the observation that the mutant Staphylococcus aureus strain expressing AgrAC199S is more susceptible to H(2)O(2) owing to repression of the antioxidant bsaA gene under oxidative stress. Together, our results show that oxidation sensing is a component of the quorum-sensing agr signaling system, which serves as an intrinsic checkpoint to ameliorate the oxidation burden caused by intense metabolic activity and potential host immune response.
authors.affiliation: Department of Chemistry and Institute for Biophysical Dynamics, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Fei
authors.initials: F
authors.lastname: Sun
authors.forename: Haihua
authors.initials: H
authors.lastname: Liang
authors.forename: Xiangqian
authors.initials: X
authors.lastname: Kong
authors.forename: Sherrie
authors.initials: S
authors.lastname: Xie
authors.forename: Hoonsik
authors.initials: H
authors.lastname: Cho
authors.forename: Xin
authors.initials: X
authors.lastname: Deng
authors.forename: Quanjiang
authors.initials: Q
authors.lastname: Ji
authors.forename: Haiyan
authors.initials: H
authors.lastname: Zhang
authors.forename: Sophie
authors.initials: S
authors.lastname: Alvarez
authors.forename: Leslie M
authors.initials: LM
authors.lastname: Hicks
authors.forename: Taeok
authors.initials: T
authors.lastname: Bae
authors.forename: Cheng
authors.initials: C
authors.lastname: Luo
authors.forename: Hualiang
authors.initials: H
authors.lastname: Jiang
authors.forename: Chuan
authors.initials: C
authors.lastname: He
mesh_terms: D000595:Amino Acid Sequence; D001426:Bacterial Proteins / Q000378:metabolism*; D003545:Cysteine / Q000378:metabolism; D004220:Disulfides / Q000378:metabolism*; D015964:Gene Expression Regulation, Bacterial / Q000235:genetics / Q000502:physiology*; D054884:Host-Pathogen Interactions / Q000502:physiology*; D013058:Mass Spectrometry; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D016296:Mutagenesis; D010084:Oxidation-Reduction; D053038:Quorum Sensing / Q000502:physiology*; D013211:Staphylococcus aureus / Q000378:metabolism* / Q000502:physiology; D015534:Trans-Activators / Q000378:metabolism*
chemical_list: C095698:Agr protein, Staphylococcus aureus; D001426:Bacterial Proteins; D004220:Disulfides; D015534:Trans-Activators; D003545:Cysteine