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Quorum-Sensing Agr Mediates Bacterial Oxidation Response Via an Intramolecular Disulfide Redox Switch in the Response Regulator Agra

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Quorum-Sensing Agr Mediates Bacterial Oxidation Response Via an Intramolecular Disulfide Redox Switch in the Response Regulator Agra Quorum-sensing agr mediates bacterial oxidation response via an intramolecular disulfide redox switch in the response regulator AgrA Fei Suna,1, Haihua Lianga,1, Xiangqian Kongb, Sherrie Xiea, Hoonsik Choc, Xin Denga, Quanjiang Jia, Haiyan Zhanga, Sophie Alvarezd, Leslie M. Hicksd, Taeok Baec, Cheng Luob, Hualiang Jiangb, and Chuan Hea,2 aDepartment of Chemistry and Institute for Biophysical Dynamics, University of Chicago, Chicago, IL 60637; bState Key Laboratory of Drug Research, Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; cDepartment of Microbiology and Immunology, Indiana University School of Medicine-Northwest, Gary, IN 46408; and dDonald Danforth Plant Science Center, St. Louis, MO 63132 Edited by Richard P. Novick, New York University School of Medicine, New York, NY, and approved April 16, 2012 (received for review January 12, 2012) Oxidation sensing and quorum sensing significantly affect bacterial virulence factor δ-toxin (Hld) but also functions as a small regu- physiology and host–pathogen interactions. However, little attention latory RNA (sRNA) per se to modulate target gene expression; has been paid to the cross-talk between these two seemingly orthog- RNAII comprises a typical bacterial TCS consisting of the sensor onal signaling pathways. Here we show that the quorum-sensing agr kinase AgrC and the response regulator AgrA. In addition, it system has a built-in oxidation-sensing mechanism through an intra- encodes AgrD, the precursor of the quorum signal that can further molecular disulfide switch possessed by the DNA-binding domain of be processed and exported as a thiolactone-containing oligopep- the response regulator AgrA. Biochemical and mass spectrometric tide autoinducer (autoinducing peptide, AIP) by the cotranscribed analysis revealed that oxidation induces the intracellular disulfide AgrB. Upon binding to the extracellular sensory domain of AgrC, bond formation between Cys-199 and Cys-228, thus leading to disso- AIP activates the kinase activity of AgrC, subsequently leading to ciation of AgrA from DNA. Molecular dynamics (MD) simulations sug- phosphorylation of the response regulator AgrA (13, 14). Phos- gest that the disulfide bond formation generates a steric clash phorylated AgrA regulates transcription of genes encoding met- responsible for the abolished DNA binding of the oxidized AgrA. abolic factors and phenol-soluble modulin (PSM) peptides (15) Mutagenesis studies further established that Cys-199 is crucial for and, more importantly, triggers the expression of the agr operon oxidation sensing. The oxidation-sensing role of Cys-199 is further by binding to the promoter regions P2 (for RNAII) and P3 (for supported by the observation that the mutant Staphylococcus aureus RNAIII), thereby forming an autoinduction genetic circuit to strain expressing AgrAC199S is more susceptible to H2O2 owing to ensure a timely rearrangement of target gene expression at a repression of the antioxidant bsaA gene under oxidative stress. To- certain threshold level of population density. gether, our results show that oxidation sensing is a component of the In addition to this prominent agr-mediated quorum sensing in quorum-sensing agr signaling system, which serves as an intrinsic S. aureus, a number of studies have demonstrated that S. aureus checkpoint to ameliorate the oxidation burden caused by intense uses oxidation-sensing global transcriptional regulators, including metabolic activity and potential host immune response. MgrA, SarZ, and SarA, to control global gene expression via the redox active Cys residue (16–19). Additionally, there are two any pathogenic bacteria are dependent on their ability to S. aureus TCSs found to be capable of sensing oxidation. One is Mswiftly sense and respond to surrounding population den- the [4Fe-4S]-containing TCS NreABC (20). NreABC is a spe- sity and changing host microenvironments. Bacterial physiologi- cialized TCS that regulates a set of genes involved in anaerobic cal rearrangements can be controlled by quorum-sensing systems nitrate/nitrite uptake but with negligible effects on virulence gene in response to increasing population density (1–3). Meanwhile, in expression (20). We also identified a [2Fe-2S]-containing redox- – the context of host pathogen interactions, host immune systems responsive TCS, AirSR, that globally impacts gene expression such as macrophages and neutrophils generate a burst of oxidants under oxygen-limited conditions (21). So far specialized regula- − • (O2 ,HO,H2O2, HClO, NO, etc.) to kill invading pathogens. tory systems have been shown to execute the oxidation-sensing Oxidation sensing, on the other hand, is exploited by pathogenic process in S. aureus independently of quorum sensing. bacteria as a key signaling strategy to adapt and evade the hostile In this work we discover that the S. aureus quorum-sensing agr – immune system (4 7). Although both quorum sensing and oxida- system has integrated another level of the signaling pathway of tion sensing have been extensively studied in bacterial pathogenesis oxidation sensing into its predominant quorum-sensing mode to and related virulence regulation (3, 8), these two distinct signaling counter oxidative stress. We demonstrate that the DNA-binding processes are often regarded as independent events in gene regu- domain of the response regulator AgrA contains a redox-active lation, and little is known about the interplay between them. Cys-199, which forms an intramolecular disulfide bond with the Staphylococcus aureus, a major human pathogen that is the most spatially proximate Cys-228 under oxidative stress. The oxidized common source of nosocomial and community-acquired infec- AgrA dissociates from its cognate DNA, leading to down-regu- tions, causes a variety of diseases, ranging from minor skin infec- lation of the expression of RNAIII and up-regulation of that of tions to life-threatening blood infections (9). The success of this bacterium in pathogenesis is largely owing to the sophisticated regulatory network composed of several global transcriptional CHEMISTRY Author contributions: F.S., H.L., and C.H. designed research; F.S., H.L., X.K., S.X., H.C., X.D., regulators (e.g., SigB, Rot, MgrA, SarA, and SarA homologs) and Q.J., and H.Z. performed research; F.S., S.A., L.M.H., T.B., C.L., and H.J. contributed new 16 two-component systems (TCSs) (e.g., agr, srrAB, arlRS, vraRS, reagents/analytic tools; F.S. and H.L. analyzed data; and F.S., H.L., and C.H. wrote hssRS,andsaeRS) (10–12), which enable the bacterium to rapidly the paper. sense and adapt to changing environment. Central to this regula- The authors declare no conflict of interest. tory network is the quorum-sensing agr system, which controls the This article is a PNAS Direct Submission. expression of bacterial virulence in response to changes in cell 1F.S. and H.L. contributed equally to this work. density (10). Transcriptional expression of the agr system gen- 2To whom correspondence should be addressed. E-mail: [email protected]. erates two adjacent mRNAs corresponding to RNAII and RNAIII This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. MICROBIOLOGY in opposite directions (Fig. 1A): RNAIII not only encodes a 1073/pnas.1200603109/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1200603109 PNAS | June 5, 2012 | vol. 109 | no. 23 | 9095–9100 Downloaded by guest on October 1, 2021 Moreover, a detailed study revealed that oxidation of C-terminal methionine in the AIP by strong oxidants including HClO and ONOO, but not mild ones such as H2O2, represses the agr regulon (23). We confirmed that millimolar levels of H2O2 could down- regulate the transcription of the agr operon (Fig. S1A) in strain Newman independently of the redox-responsive SarA (24, 25), another global transcriptional regulator required for agr expres- sion (26). Repression of RNAIII upon H2O2 treatment was ob- served in S. aureus strain Newman as well as in USA300 (Fig. S2A). Clearly, the model of AIP inactivation by oxidation, which is mainly responsible for extracellular factors that influence the agr regulation, accounts for the response of the agr system to certain types of reactive oxygen/nitrogen species (ROS/RNS), which prompted us to identify an alternative mechanism un- derlying the redox response of agr toward the most common H2O2 stress that S. aureus encounters. The solved crystal structure of the DNA-binding domain of the response regulator AgrA complexed with DNA (27) shows a unique topology with 10 β-strands arranged into three antipar- allel β-sheets and three small α-helices (Fig. 1B). Intriguingly, a close view of the crystal structure reveals two spatially proximate Cys residues, Cys-199 and Cys-228, residing in strands β6 and β10, respectively (Fig. 1B). The two sulfur atoms are approximately separated by 4.2 Å (Fig. 1B), an arrangement suggesting the presence of an intracellular disulfide switch similar to the OxyR type regulators (28, 29). However, the corresponding sulfur atoms in the reduced OxyR (Cys-199 and Cys-208) are ∼17 Å away from each other, far more separated than that of AgrA (30). The much shorter distance between Cys-199 and Cys-228 in AgrA makes the oxidation-induced formation of the disulfide bond highly con- ceivable. Given that the disulfide bond formation has been ob- served in many oxidation-sensing/defense proteins in addition to OxyR (31–34), we envisioned that this prospective disulfide switch might also play critical roles in redox regulation (Fig. 1A). Oxidation Leads to Dissociation of AgrA from DNA. To substantiate that AgrA is responsive to oxidation, we cloned, expressed, and purified the DNA-binding domain of AgrA (Fig. S3) and ex- amined its DNA-binding activity in the absence or presence of Fig. 1. S. aureus AgrA. (A) Model of gene regulation by the quorum-sensing H2O2 (unless mentioned otherwise, we use AgrA to refer to the agr. AIP, with its thiolactone structure, is encoded by agrD, processed, and truncated version of this protein containing residues 137–238 for exported by AgrB.
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