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Moonlighting chaperone activity of the enzyme PqsE contributes to RhlR-controlled virulence of Pseudomonas aeruginosa
Nature Communications ( IF 14.7 ) Pub Date : 2022-12-01 , DOI: 10.1038/s41467-022-35030-w
Sebastian Roman Borgert 1 , Steffi Henke 1 , Florian Witzgall 1 , Stefan Schmelz 1 , Susanne Zur Lage 1 , Sven-Kevin Hotop 2 , Steffi Stephen 2 , Dennis Lübken 3 , Jonas Krüger 4 , Nicolas Oswaldo Gomez 4 , Marco van Ham 5 , Lothar Jänsch 5 , Markus Kalesse 3 , Andreas Pich 6 , Mark Brönstrup 2 , Susanne Häussler 4 , Wulf Blankenfeldt 1, 7
Affiliation  

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.



中文翻译:

PqsE 酶的兼职伴侣活性有助于 RhlR 控制的铜绿假单胞菌毒力

铜绿假单胞菌是医院感染的主要原因,也会导致囊性纤维化或慢性阻塞性肺病的严重恶化。三个相互交织的群体感应系统控制铜绿假单胞菌的毒力,其中rhl回路在晚期和慢性感染中起主导作用。rhl转录因子 RhlR控制的大多数性状都依赖于 PqsE,PqsE 是假单胞菌喹诺酮信号 (PQS) 生物合成中可有可无的硫酯酶,它通过可能涉及两种蛋白质直接相互作用的神秘机制干扰 RhlR。在这里,我们证明 PqsE 和 RhlR 形成 2:2 蛋白质复合物,与 RhlR 激动剂N-丁酰基-L-高丝氨酸内酯 (C4-HSL) 一起溶解 RhlR,从而使原本不溶的转录因子变得活跃。我们确定了复合物的晶体结构并确定了相互作用所必需的残基。为了证实 PqsE 的伴侣样活性,我们设计了 RhlR 的稳定性优化变体,其在激活铜绿假单胞菌PqsE/RhlR 控制过程时无需 C4-HSL 和 PqsE 。总之,我们的数据提供了对 PqsE 独特调节作用的深入了解,并为开发新的铜绿假单胞菌特异性药物奠定了基础。

更新日期:2022-12-01
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