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

Sebastian Roman Borgert, Steffi Henke, Florian Witzgall, Stefan Schmelz, Susanne zur Lage, Sven-Kevin Hotop, Steffi Stephen, Dennis Lübken, Jonas Krüger, Nicolas Oswaldo Gomez, Marco Ham, Lothar Jänsch, Markus Kalesse, Andreas Pich, Mark Brönstrup, Susanne Häussler and Wulf Blankenfeldt ()
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Sebastian Roman Borgert: Helmholtz Centre for Infection Research
Steffi Henke: Helmholtz Centre for Infection Research
Florian Witzgall: Helmholtz Centre for Infection Research
Stefan Schmelz: Helmholtz Centre for Infection Research
Susanne zur Lage: Helmholtz Centre for Infection Research
Sven-Kevin Hotop: Helmholtz Centre for Infection Research
Steffi Stephen: Helmholtz Centre for Infection Research
Dennis Lübken: Leibniz University Hannover
Jonas Krüger: Helmholtz Centre for Infection Research
Nicolas Oswaldo Gomez: Helmholtz Centre for Infection Research
Marco Ham: Helmholtz Centre for Infection Research
Lothar Jänsch: Helmholtz Centre for Infection Research
Markus Kalesse: Leibniz University Hannover
Andreas Pich: Core Facility Proteomics, Hannover Medical School
Mark Brönstrup: Helmholtz Centre for Infection Research
Susanne Häussler: Helmholtz Centre for Infection Research
Wulf Blankenfeldt: Helmholtz Centre for Infection Research

Nature Communications, 2022, vol. 13, issue 1, 1-12

Abstract: Abstract 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.

Date: 2022
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DOI: 10.1038/s41467-022-35030-w

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