MvfR, a key Pseudomonas aeruginosa pathogenicity LTTR-class regulatory protein, has dual ligands

Authors

  • Gaoping Xiao,

    1. Department of Surgery, Harvard Medical School, Massachusetts General Hospital, and Shriner's Burns Institute Boston, MA 02114, USA.
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  • Eric Déziel,

    1. Department of Surgery, Harvard Medical School, Massachusetts General Hospital, and Shriner's Burns Institute Boston, MA 02114, USA.
    2. INRS-Institut Armand-Frappier, Laval, Québec, Canada H7V 1B7, Canada.
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  • Jianxin He,

    1. Department of Surgery, Harvard Medical School, Massachusetts General Hospital, and Shriner's Burns Institute Boston, MA 02114, USA.
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  • François Lépine,

    1. INRS-Institut Armand-Frappier, Laval, Québec, Canada H7V 1B7, Canada.
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  • Biliana Lesic,

    1. Department of Surgery, Harvard Medical School, Massachusetts General Hospital, and Shriner's Burns Institute Boston, MA 02114, USA.
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  • Marie-Hélène Castonguay,

    1. INRS-Institut Armand-Frappier, Laval, Québec, Canada H7V 1B7, Canada.
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  • Sylvain Milot,

    1. INRS-Institut Armand-Frappier, Laval, Québec, Canada H7V 1B7, Canada.
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  • Anastasia P. Tampakaki,

    1. Department of Surgery, Harvard Medical School, Massachusetts General Hospital, and Shriner's Burns Institute Boston, MA 02114, USA.
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    • Present address: Agricultural University of Athens, Athens, Greece.

  • Scott E. Stachel,

    1. Department of Surgery, Harvard Medical School, Massachusetts General Hospital, and Shriner's Burns Institute Boston, MA 02114, USA.
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  • Laurence G. Rahme

    Corresponding author
    1. Department of Surgery, Harvard Medical School, Massachusetts General Hospital, and Shriner's Burns Institute Boston, MA 02114, USA.
      *E-mail rahme@amber.mgh.harvard.edu; Tel. (+1) 617 724 5003; Fax (+1) 617 724 8558.
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*E-mail rahme@amber.mgh.harvard.edu; Tel. (+1) 617 724 5003; Fax (+1) 617 724 8558.

Summary

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-2-heptylquinoline (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 HHQ 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.

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