Moonlighting chaperone activity of the enzyme PqsE contributes to RhlR-controlled virulence of Pseudomonas aeruginosa

Pseudomonas aeruginosa is a major cause of nosocomial infections and also leads to severe exacerbations in cystic fibrosis or chronic obstructive pulmonary disease. Three intertwined quorum sensing systems control virulence of P. aeruginosa , with the rhl circuit playing the leading role in late and...

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Veröffentlicht in:Nature communications 2022-12, Vol.13 (1), p.7402-12, Article 7402
Hauptverfasser: Borgert, Sebastian Roman, Henke, Steffi, Witzgall, Florian, Schmelz, Stefan, zur Lage, Susanne, Hotop, Sven-Kevin, Stephen, Steffi, Lübken, Dennis, Krüger, Jonas, Gomez, Nicolas Oswaldo, van Ham, Marco, Jänsch, Lothar, Kalesse, Markus, Pich, Andreas, Brönstrup, Mark, Häussler, Susanne, Blankenfeldt, Wulf
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Sprache:eng
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Zusammenfassung:Pseudomonas aeruginosa is a major cause of nosocomial infections and also leads to severe exacerbations in cystic fibrosis or chronic obstructive pulmonary disease. Three intertwined quorum sensing systems control virulence of P. aeruginosa , with the rhl circuit playing the leading role in late and chronic infections. The majority of traits controlled by rhl transcription factor RhlR depend on PqsE, a dispensable thioesterase in Pseudomonas Quinolone Signal (PQS) biosynthesis that interferes with RhlR through an enigmatic mechanism likely involving direct interaction of both proteins. Here we show that PqsE and RhlR form a 2:2 protein complex that, together with RhlR agonist N -butanoyl-L-homoserine lactone (C4-HSL), solubilizes RhlR and thereby renders the otherwise insoluble transcription factor active. We determine crystal structures of the complex and identify residues essential for the interaction. To corroborate the chaperone-like activity of PqsE, we design stability-optimized variants of RhlR that bypass the need for C4-HSL and PqsE in activating PqsE/RhlR-controlled processes of P. aeruginosa . Together, our data provide insight into the unique regulatory role of PqsE and lay groundwork for developing new P. aeruginosa -specific pharmaceuticals. Interplay of enzyme PqsE and transcription factor RhlR controls the virulence of Pseudomonas aeruginosa . Here, the authors show that complex formation with PqsE stabilizes RhlR in a soluble active state. PqsE/RhlR complex structures provide a basis for drug discovery against this important pathogen.\
ISSN:2041-1723
2041-1723
DOI:10.1038/s41467-022-35030-w