Burkholderia cenocepacia integrates cis -2-dodecenoic acid and cyclic dimeric guanosine monophosphate signals to control virulence

Abstract

Quorum sensing (QS) signals are used by bacteria to regulate biological functions in response to cell population densities. Cyclic diguanosine monophosphate (c-di-GMP) regulates cell functions in response to diverse environmental chemical and physical signals that bacteria perceive. In , the QS signal receptor RpfR degrades intracellular c-di-GMP when it senses the QS signal-2-dodecenoic acid, also called diffusible signal factor (BDSF), as a proxy for high cell density. However, it was unclear how this resulted in control of BDSF-regulated phenotypes. Here, we found that RpfR forms a complex with a regulator named GtrR (BCAL1536) to enhance its binding to target gene promoters under circumstances where the BDSF signal binds to RpfR to stimulate its c-di-GMPphosphodiesterase activity. In the absence of BDSF, c-di-GMP binds to the RpfR-GtrR complex and inhibits its ability to control gene expression. Mutations in and had overlapping effects on both the transcriptome and BDSF-regulated phenotypes, including motility, biofilm formation, and virulence. These results show that RpfR is a QS signal receptor that also functions as a c-di-GMP sensor. This protein thus allows to integrate information about its physical and chemical surroundings as well as its population density to control diverse biological functions including virulence. This type of QS system appears to be widely distributed in beta and gamma proteobacteria.

Metatranscriptomic analysis of an in vitro biofilm model reveals strain-specific interactions among multiple bacterial species

“…Here we attempted to link the expression changes of QS related genes with the changes in virulence factors. Cyclic diguanylate monophosphate (c-di-GMP) is an important global signaling molecule that can regulate diverse bacterial physiological processes through its downstream receptors such as biofilm formation [39] and virulence [40,41]. However, c-di-GMP and c-di-AMP signaling have been rarely studied in oral biofilms [42].…”

Disruption of Quorum Sensing and Virulence in Burkholderia cenocepacia by a Structural Analogue of the cis -2-Dodecenoic Acid Signal

“…requires targeting the upstream region of the QS signals. Among these factors, RpfFR homologues function as the master QS regulators within Burkholderia QS pathways (11,32,40). Moreover, these homologs display high sequence similarity and structural similarity (28), making them attractive targets for Burkholderia QS inhibition.…”

“…14-Me-C 16:⌬2 decreases AHL signal production. Recent studies showed that the BDSF system controls AHL signal production by regulating the expression of the AHL synthase CepI at the transcriptional level (9,11). We next sought to measure AHL signal production in the wild-type H111 strain in the presence or absence of 14-Me-C 16:Δ2 .…”

“…Significant differences (*, P Ͻ 0.05; **, P Ͻ 0.01; ***, P Ͻ 0.001) between the tested compound and its control (n ϭ 3) are shown. employ the BDSF system to regulate biological functions (11,28,32,33). Therefore, the effect of 14-Me-C 16:Δ2 on the QS-regulated phenotypes of different Burkholderia species was investigated.…”

A novel two‐component system modulates quorum sensing and pathogenicity in Burkholderia cenocepacia

“…The BDSF system relies on the biosynthesis of BDSF signals by the bifunctional crotonase RpfF Bc and the BDSF receptor protein RpfR, which contains PAS‐GGDEF‐EAL domains (Boon et al ., ; Bi et al ., ; Deng et al ., ). BDSF signals bind to RpfR and stimulate cyclic dimeric guanosine monophosphate (c‐di‐GMP) phosphodiesterase activity, thus decreasing intracellular c‐di‐GMP levels and consequently modulating the transcription of target genes by activating the RpfR‐GtrR complex (Deng et al ., ; Udine et al ., ; Yang et al ., ). The BDSF system controls many biological functions in conjunction with the CepIR system (Schmid et al ., ; Deng et al ., ).…”