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    Pseudomonas aeruginosa Alkyl quinolones repress hypoxia-inducible factor 1 (HIF-1) signaling through HIF-1a degradation

    Access Status
    Open access via publisher
    Authors
    Legendre, C.
    Reen, F.
    Mooij, M.
    McGlacken, G.
    Adams, C.
    O'Gara, Fergal
    Date
    2012
    Type
    Journal Article
    
    Metadata
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    Citation
    Legendre, C. and Reen, F. and Mooij, M. and McGlacken, G. and Adams, C. and O'Gara, F. 2012. Pseudomonas aeruginosa Alkyl quinolones repress hypoxia-inducible factor 1 (HIF-1) signaling through HIF-1a degradation. Infection and Immunity. 80 (11): pp. 3985-3992.
    Source Title
    Infection and Immunity
    DOI
    10.1128/IAI.00554-12
    ISSN
    0019-9567
    URI
    http://hdl.handle.net/20.500.11937/22150
    Collection
    • Curtin Research Publications
    Abstract

    The transcription factor hypoxia-inducible factor 1 (HIF-1) has recently emerged to be a crucial regulator of the immune response following pathogen perception, including the response to the important human pathogen Pseudomonas aeruginosa. However, as mechanisms involved in HIF-1 activation by bacterial pathogens are not fully characterized, understanding how bacteria and bacterial compounds impact on HIF-1α stabilization remains a major challenge. In this context, we have focused on the effect of secreted factors of P. aeruginosa on HIF-1 regulation. Surprisingly, we found that P. aeruginosa cell-free supernatant significantly repressed HIF-1α protein levels. Further characterization revealed that HIF-1α downregulation was dependent on a subset of key secreted factors involved in P. aeruginosa pathogenesis, the 2-alkyl-4-quinolone (AQ) quorum sensing (QS) signaling molecules, and in particular the pseudomonas quinolone signal (PQS). Under hypoxic conditions, the AQ-dependent downregulation of HIF-1α was linked to the suppressed induction of the important HIF-1 target gene hexokinase II. Furthermore, we demonstrated that AQ molecules directly target HIF-1α protein degradation through the 26S-proteasome proteolytic pathway but independently of the prolyl hydroxylase domain (PHD). In conclusion, this is the first report showing that bacterial molecules can repress HIF-1α protein levels. Manipulation of HIF-1 signaling by P. aeruginosa AQs could have major consequences for the host response to infection and may facilitate the infective properties of this pathogen.

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