MvfR, a key Pseudomonas aeruginosa pathogenicity LTTR-class regulatory protein, has dual ligands.
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.
Xiao
Gaoping
G
Department of Surgery, Harvard Medical School, Massachusetts General Hospital, USA.
Déziel
Eric
E
He
Jianxin
J
Lépine
François
F
Lesic
Biliana
B
Castonguay
Marie-Hélène
MH
Milot
Sylvain
S
Tampakaki
Anastasia P
AP
Stachel
Scott E
SE
Rahme
Laurence G
LG
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
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