Quorum-sensing agr mediates bacterial oxidation response via an intramolecular disulfide redox switch in the response regulator AgrA

Fei Sun, Haihua Liang, Xiangqian Kong, Sherrie Xie, Hoonsik Cho, Xin Deng, Quanjiang Ji, Haiyan Zhang, Sophie Alvarez, Leslie M. Hicks, Taeok Bae, Cheng Luo, Hualiang Jiang, Chuan He

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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. Herewe showthat 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 2O2 owing to repression of the antioxidant bsaA gene under oxidative stress. Together, our results showthat 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.

Original languageEnglish (US)
Pages (from-to)9095-9100
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume109
Issue number23
DOIs
Publication statusPublished - Jun 5 2012

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