title: Investigation of the Staphylococcus aureus GraSR regulon reveals novel links to virulence, stress response and cell wall signal transduction pathways.
abstract: The GraS/GraR two-component system has been shown to control cationic antimicrobial peptide (CAMP) resistance in the major human pathogen Staphylococcus aureus. We demonstrated that graX, also involved in CAMP resistance and cotranscribed with graRS, encodes a regulatory cofactor of the GraSR signaling pathway, effectively constituting a three-component system. We identified a highly conserved ten base pair palindromic sequence (5' ACAAA TTTGT 3') located upstream from GraR-regulated genes (mprF and the dlt and vraFG operons), which we show to be essential for transcriptional regulation by GraR and induction in response to CAMPs, suggesting it is the likely GraR binding site. Genome-based predictions and transcriptome analysis revealed several novel GraR target genes. We also found that the GraSR TCS is required for growth of S. aureus at high temperatures and resistance to oxidative stress. The GraSR system has previously been shown to play a role in S. aureus pathogenesis and we have uncovered previously unsuspected links with the AgrCA peptide quorum-sensing system controlling virulence gene expression. We also show that the GraSR TCS controls stress reponse and cell wall metabolism signal transduction pathways, sharing an extensive overlap with the WalKR regulon. This is the first report showing a role for the GraSR TCS in high temperature and oxidative stress survival and linking this system to stress response, cell wall and pathogenesis control pathways.
authors.affiliation: Department of Microbiology, Institut Pasteur, Biology of Gram-Positive Pathogens, Paris, France.
authors.forename: Mélanie
authors.initials: M
authors.lastname: Falord
authors.forename: Ulrike
authors.initials: U
authors.lastname: Mäder
authors.forename: Aurélia
authors.initials: A
authors.lastname: Hiron
authors.forename: Michel
authors.initials: M
authors.lastname: Débarbouillé
authors.forename: Tarek
authors.initials: T
authors.lastname: Msadek
mesh_terms: D023181:Antimicrobial Cationic Peptides / Q000494:pharmacology; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism; D001483:Base Sequence; D001665:Binding Sites; D002473:Cell Wall / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D003091:Colistin / Q000494:pharmacology; D016384:Consensus Sequence / Q000235:genetics; D024881:Drug Resistance, Bacterial / Q000187:drug effects / Q000235:genetics; D020869:Gene Expression Profiling; D015964:Gene Expression Regulation, Bacterial / Q000187:drug effects; D005798:Genes, Bacterial / Q000235:genetics; D006706:Homeostasis / Q000187:drug effects; D006801:Humans; D008969:Molecular Sequence Data; D009876:Operon / Q000235:genetics; D018384:Oxidative Stress / Q000187:drug effects / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding / Q000187:drug effects; D018085:Regulon / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics*; D013211:Staphylococcus aureus / Q000187:drug effects / Q000235:genetics* / Q000254:growth & development / Q000472:pathogenicity*; D013312:Stress, Physiological / Q000187:drug effects / Q000235:genetics*; D013696:Temperature; D014774:Virulence / Q000187:drug effects / Q000235:genetics
chemical_list: D023181:Antimicrobial Cationic Peptides; D001426:Bacterial Proteins; D003091:Colistin