title: MvfR, a key Pseudomonas aeruginosa pathogenicity LTTR-class regulatory protein, has dual ligands.
abstract: MvfR (PqsR), a Pseudomonas aeruginosa LysR-type transcriptional regulator, plays a critical role in the virulence of this pathogen. MvfR modulates the expression of multiple quorum sensing (QS)-regulated virulence factors; and the expression of the phnAB and pqsA-E genes that encode functions mediating 4-hydroxy-2-alkylquinolines (HAQs) signalling compounds biosynthesis, including 3,4-dihydroxy-2heptylquinoline (PQS) and its precursor 4-hydroxy-2-heptylquinoline (HHQ). PQS enhances the in vitro DNA-binding affinity of MvfR to the pqsA-E promoter, to suggest it might function as the in vivo MvfR ligand. Here we identify a novel MvfR ligand, as we show that HHQ binds to the MvfR ligand-binding-domain and potentiates MvfR binding to the pqsA-E promoter leading to transcriptional activation of pqsA-E genes. We show that HHQ is highly produced in vivo, where it is not fully converted into PQS, and demonstrate that it is required for MvfR-dependent gene expression and pathogenicity; PQS is fully dispensable, as pqsH-mutant cells, which produce HHI but completely lack PQS, display normal MvfR-dependent gene expression and virulence. Conversely, PQS is required for full production of pyocyanin. These results uncover a novel biological role for HHQ; and provide novel insights on MvfR activation that may aid in the development of therapies that prevent or treat P. aeruginosa infections in humans.
authors.affiliation: Department of Surgery, Harvard Medical School, Massachusetts General Hospital, USA.
authors.forename: Gaoping
authors.initials: G
authors.lastname: Xiao
authors.forename: Eric
authors.initials: E
authors.lastname: Déziel
authors.forename: Jianxin
authors.initials: J
authors.lastname: He
authors.forename: François
authors.initials: F
authors.lastname: Lépine
authors.forename: Biliana
authors.initials: B
authors.lastname: Lesic
authors.forename: Marie-Hélène
authors.initials: MH
authors.lastname: Castonguay
authors.forename: Sylvain
authors.initials: S
authors.lastname: Milot
authors.forename: Anastasia P
authors.initials: AP
authors.lastname: Tampakaki
authors.forename: Scott E
authors.initials: SE
authors.lastname: Stachel
authors.forename: Laurence G
authors.initials: LG
authors.lastname: Rahme
mesh_terms: D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D024202:Electrophoretic Mobility Shift Assay; D015964:Gene Expression Regulation, Bacterial; D008024:Ligands; D051379:Mice; D009154:Mutation; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D011487:Protein Conformation; D011552:Pseudomonas Infections / Q000382:microbiology / Q000401:mortality; D011550:Pseudomonas aeruginosa / Q000235:genetics / Q000378:metabolism* / Q000472:pathogenicity; D011804:Quinolines / Q000737:chemistry / Q000378:metabolism; D015363:Quinolones / Q000737:chemistry / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D015996:Survival Rate; D013997:Time Factors; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014774:Virulence / Q000235:genetics
chemical_list: C407944:2-heptyl-3-hydroxy-4-quinolone; D001426:Bacterial Proteins; D004268:DNA-Binding Proteins; C080365:LasR protein, Pseudomonas aeruginosa; D008024:Ligands; D011804:Quinolines; D015363:Quinolones; D015534:Trans-Activators; D014157:Transcription Factors; C073470:LysR protein, Bacteria