title: Pseudomonas aeruginosa Alkyl quinolones repress hypoxia-inducible factor 1 (HIF-1) signaling through HIF-1α degradation.
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.
authors.affiliation: BIOMERIT Research Centre, Department of Microbiology, University College Cork, Cork, Ireland.
authors.forename: Claire
authors.initials: C
authors.lastname: Legendre
authors.forename: F Jerry
authors.initials: FJ
authors.lastname: Reen
authors.forename: Marlies J
authors.initials: MJ
authors.lastname: Mooij
authors.forename: Gerard P
authors.initials: GP
authors.lastname: McGlacken
authors.forename: Claire
authors.initials: C
authors.lastname: Adams
authors.forename: Fergal
authors.initials: F
authors.lastname: O'Gara
mesh_terms: D042462:4-Quinolones / Q000378:metabolism*; D015153:Blotting, Western; D002478:Cells, Cultured; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000378:metabolism*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D011550:Pseudomonas aeruginosa / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology
chemical_list: D042462:4-Quinolones; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit