Department of Molecular Biology, Princeton University, Princeton, NJ 08544.
Department of Pediatrics, Emory University School of Medicine, Children's Healthcare of Atlanta, Inc., Atlanta, GA 30322.
Proc Natl Acad Sci U S A. 2018 Oct 2;115(40):E9411-E9418. doi: 10.1073/pnas.1814023115. Epub 2018 Sep 17.
is a leading cause of life-threatening nosocomial infections. Many virulence factors produced by are controlled by the cell-to-cell communication process called quorum sensing (QS). QS depends on the synthesis, release, and groupwide response to extracellular signaling molecules called autoinducers. possesses two canonical LuxI/R-type QS systems, LasI/R and RhlI/R, that produce and detect 3OC12-homoserine lactone and C4-homoserine lactone, respectively. Previously, we discovered that RhlR regulates both RhlI-dependent and RhlI-independent regulons, and we proposed that an alternative ligand functions together with RhlR to control the target genes in the absence of RhlI. Here, we report the identification of an enzyme, PqsE, which is the alternative-ligand synthase. Using biofilm analyses, reporter assays, site-directed mutagenesis, protein biochemistry, and animal infection studies, we show that the PqsE-produced alternative ligand is the key autoinducer that promotes virulence gene expression. Thus, PqsE can be targeted for therapeutic intervention. Furthermore, this work shows that PqsE and RhlR function as a QS-autoinducer synthase-receptor pair that drives group behaviors in .
是危及生命的医院获得性感染的主要原因。许多由 产生的毒力因子受称为群体感应 (QS) 的细胞间通讯过程控制。QS 依赖于合成、释放和群体对称为自诱导物的细胞外信号分子的反应。 拥有两个典型的 LuxI/R 型 QS 系统，LasI/R 和 RhlI/R，分别产生和检测 3OC12-同型高丝氨酸内酯和 C4-同型高丝氨酸内酯。以前，我们发现 RhlR 调节 RhlI 依赖和 RhlI 独立的调控子，我们提出替代配体与 RhlR 一起在没有 RhlI 的情况下控制靶基因。在这里，我们报告了一种酶 PqsE 的鉴定，它是替代配体合成酶。通过生物膜分析、报告基因检测、定点突变、蛋白质生物化学和动物感染研究，我们表明 PqsE 产生的替代配体是促进毒力基因表达的关键自诱导物。因此，PqsE 可以成为治疗干预的目标。此外，这项工作表明 PqsE 和 RhlR 作为 QS-自诱导物合成酶-受体对在 中发挥作用，驱动群体行为。
