Pseudomonas aeruginosa Alkyl Quinolones Signaling through HIF-1a Degradation Repress Hypoxia-Inducible Factor 1 (HIF-1)

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-1 stabilization remains a major challenge. In this context, we have focused onbr /> the effect of secreted factors of P. aeruginosa on HIF-1 regulation. Surprisingly, we found that P. aeruginosa cell-free supernatantbr /> significantly repressed HIF-1 protein levels. Further characterization revealed that HIF-1 downregulation was dependentbr /> on a subset of key secreted factors involved in P. aeruginosa pathogenesis, the 2-alkyl-4-quinolone (AQ) quorum sensing (QS)br /> signaling molecules, and in particular the pseudomonas quinolone signal (PQS). Under hypoxic conditions, the AQ-dependentbr /> downregulation of HIF-1 was linked to the suppressed induction of the important HIF-1 target gene hexokinase II. Furthermore,br /> we demonstrated that AQ molecules directly target HIF-1 protein degradation through the 26S-proteasome proteolyticbr /> pathway but independently of the prolyl hydroxylase domain (PHD). In conclusion, this is the first report showing that bacterialbr /> molecules can repress HIF-1 protein levels. Manipulation of HIF-1 signaling by P. aeruginosa AQs could have major consequencesbr /> for the host response to infection and may facilitate the infective properties of this pathogen./p