Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.3.1.184 (LasR)
 897 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Bacterial quorum sensing using acyl-homoserine lactones (acyl-HSLs) as cell-density dependent signalling molecules is important for the transcriptional regulation of many genes essential in the establishment and the maintenance of bacteria-host associations. Vibrio fischeri, the symbiotic partner of the Hawaiian bobtail squid Euprymna scolopes, possesses two distinct acyl-HSL synthase proteins, LuxI and AinS. Whereas the cell density-dependent regulation of luminescence by the LuxI-produced signal is a well-described phenomenon, and its role in light organ symbiosis has been defined, little is known about the ain system. We have investigated the impact of the V. fischeri acyl-HSL synthase AinS on both luminescence and symbiotic colonization. Through phenotypic studies of V. fischeri mutants we have found that the AinS-signal is the predominant inducer of luminescence expression in culture, whereas the impact of the LuxI-signal is apparent only at the high cell densities occurring in symbiosis. Furthermore, our studies revealed that ainS regulates activities essential for successful colonization of E. scolopes, i.e. the V. fischeri ainS mutant failed to persist in the squid light organ. Mutational inactivation of the transcriptional regulator protein LuxO in the ainS mutant partially or completely reversed all the observed phenotypes, demonstrating that the AinS-signal regulates expression of downstream genes through the inactivation of LuxO. Taken together, our results suggest that the two quorum-sensing systems in V. fischeri, ain and lux, sequentially induce the expression of luminescence genes and possibly other colonization factors.
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PMID:The Vibrio fischeri quorum-sensing systems ain and lux sequentially induce luminescence gene expression and are important for persistence in the squid host. 1450 83

In Pseudomonas aeruginosa, virulence determinants and biofilm formation are coordinated via a hierarchical quorum sensing cascade, which involves the transcriptional regulators LasR and RhlR and their cognate homoserine lactone activators C12-HSL [N-(3-oxododecanoyl)-L-homoserine lactone] and c4-hsl (n-butanoyl-L-homoserine lactone), which are produced by LasI and RhlI, respectively. The exoenzyme S regulon of P. aeruginosa, comprises genes for a type III secretion system and for four anti-host effector proteins (ExoS, T, U and Y), which are translocated into host cells. It is a reasonable assumption that this ExoS regulon should be downregulated in the biofilm growth state and thus should also be under the regulatory control of the Las/Rhl system. Therefore, an exoS'-gfp reporter construct was used, and the influence of the Las and Rhl quorum sensing systems and the effect of the stationary-phase sigma factor RpoS on regulation of the exoS gene was examined. Evidence is provided for downregulation of exoS during biofilm formation of P. aeruginosa PAO1. The rhlI mutant PDO100 and rhlR mutant PDO111, but not the lasI mutant PDO-JP1, showed approximately twofold upregulation of the exoS'-gfp reporter in comparison to PAO1. Upregulation of exoS'-gfp in the PDO100 mutant could be repressed to normal level by adding C4-HSL autoinducer, indicating a negative regulatory effect of RhlR/C4-HSL on exoS expression. As RhlR/C4-HSL is also involved in regulation of RpoS, the P. aeruginosa rpoS mutant SS24 was examined and the exoS'-gfp reporter was found to be fivefold upregulated in comparison to PAO1. For the first time evidence is reported for a regulatory cascade linking RhlR/RhlI and RpoS with the expression of the anti-host effector ExoS, part of the exoenzyme S regulon. Moreover, these data suggest that the exoenzyme S regulon may be downregulated in P. aeruginosa biofilms.
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PMID:Expression of Pseudomonas aeruginosa exoS is controlled by quorum sensing and RpoS. 1507 94

Many gram-negative bacteria employ N-acylhomoserine lactones (AHL) to regulate diverse physiological processes in concert with cell population density (quorum sensing [QS]). In the plant pathogen Erwinia carotovora, the AHL synthesized via the carI/expI genes are responsible for regulating the production of secreted plant cell wall-degrading exoenzymes and the antibiotic carbapen-3-em carboxylic acid. We have previously shown that targeting the product of an AHL synthase gene (yenI) from Yersinia enterocolitica to the chloroplasts of transgenic tobacco plants caused the synthesis in planta of the cognate AHL signaling molecules N-(3-oxohexanoyl)-L-homoserine lactone (3-oxo-C6-HSL) and N-hexanoylhomoserine lactone (C6-HSL), which in turn, were able to complement a carI-QS mutant. In the present study, we demonstrate that transgenic potato plants containing the yenI gene are also able to express AHL and that the presence and level of these AHL in the plant increases susceptibility to infection by E. carotovora. Susceptibility is further affected by both the bacterial level and the plant tissue under investigation.
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PMID:Potato plants genetically modified to produce N-acylhomoserine lactones increase susceptibility to soft rot erwiniae. 1530 9

Bacteria commonly use diffusible signal molecules to synchronise their behaviour by facilitating population dependent co-ordination. This cell-to-cell signalling mechanism is known as quorum sensing (QS) and provides a way of ensuring that certain genes are 'switched on' only when a certain signal concentration (typically corresponding to a large population density) has been reached. In this paper we focus on the QS system of the human pathogen Pseudomonas aeruginosa, which employs a complex hierarchy of QS signalling systems, which regulate the formation of multiple exoproducts, swarming and biofilm differentiation. In P. aeruginosa, the signal molecules are N-acylated homoserine lactones (AHLs; e.g., N-(3-oxododecanoyl)-homoserine lactone [3-oxo-C12-HSL]), which bind to transcriptional regulator proteins (LasR in the case of 3-oxo-C12-HSL) to activate the expression of target genes including lasI, which codes for the 3-oxo-C12-HSL synthase. Since the virulence of P. aeruginosa is controlled by QS, agents (QSBs) designed to block this cell-to-cell communication have potential as novel antibacterials. By drawing on existing models for the reaction kinetics of this system, we model a growing population subject to treatment with two kinds of QSB, together with a conventional antibiotic. The first kind of QSB is assumed to act by diffusing through the cell membrane and then destabilising/sequestering LasR, while the second kind remains outside the cell and degrades the AHL signal molecule itself. Numerical and mathematical analysis of the resulting systems of ordinary differential equations reveals in particular that, while a sufficiently high dose of QSB is, in all cases considered, able to reduce the AHL concentration (and hence virulence) to a negligible level, the qualitative response to treatment is sensitive to parameter values.
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PMID:Mathematical modelling of therapies targeted at bacterial quorum sensing. 1549 75

Burkholderia glumae BGR1 produces a broad-host range phytotoxin, called toxoflavin, which is a key pathogenicity factor in rice grain rot and wilt in many field crops. Our molecular and genetic analyses of toxoflavin-deficient mutants demonstrated that gene clusters for toxoflavin production consist of four transcriptional units. The toxoflavin biosynthesis genes were composed of five genes, toxA to toxE, as Suzuki et al. (2004) reported previously. Genes toxF to toxI, which are responsible for toxoflavin transport, were polycistronic and similar to the genes for resistance-nodulation-division (RND) efflux systems. Using Tn3-gusA reporter fusions, we found that ToxR, a LysR-type regulator, regulates both the toxABCDE and toxFGHI operons in the presence of toxoflavin as a coinducer. In addition, the expression of both operons required a transcriptional activator, ToxJ, whose expression is regulated by quorum sensing. TofI, a LuxI homologue, was responsible for the biosynthesis of both N-hexanoyl homoserine lactone and N-octanoyl homoserine lactone (C8-HSL). C8-HSL and its cognate receptor TofR, a LuxR homologue, activated toxJ expression. This is the first report that quorum sensing is involved in pathogenicity by the regulation of phytotoxin biosynthesis and its transport in plant pathogenic bacteria.
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PMID:Quorum sensing and the LysR-type transcriptional activator ToxR regulate toxoflavin biosynthesis and transport in Burkholderia glumae. 1552 77

Aeromonas hydrophila is a pathogen of fish, amphibians and humans which produces N-acylhomoserine lactone quorum sensing signal molecules and possesses homologues of the Vibrio fischeri luxI and luxR quorum sensing genes termed ahyI and ahyR, respectively. The ahyI and ahyR genes of A. hydrophila comprise a divergon with a 62 bp intergenic region and control biofilm maturation and extracellular protease production. Stationary phase culture supernatants from an ahyR but not an ahyI mutant contain N-butanoylhomoserine lactone (C4-HSL) which is shown to be required for maximal ahyI expression. To determine whether AhyR regulates ahyI, the expression of AhyI was followed throughout growth by Western blot analysis. This revealed that AhyI can be detected in the exponential phase but appears to be degraded in stationary phase in the parent A. hydrophila strain. In an ahyR mutant however, the AhyI protein is only produced in stationary phase but production is sustained suggesting that AhyR controls the timing of AhyI production and turnover. By using RT-PCR, we mapped the transcriptional start site of ahyI which revealed that the 12 bp symmetrical lux-box like sequence present in the 62 bp ahyRI intergenic region overlaps with the -10 region of the ahyI promoter. To determine whether AhyR could bind to the ahyRI intergenic region, the ahyR gene was expressed and purified as a maltose binding protein (MalE) fusion. Electrophoretic mobility shift assays demonstrated that MalE-AhyR specifically bound to this sequence in both the presence and absence of N-butanoylhomoserine lactone (C4-HSL). Taken together, these data suggest that AhyR acts as both a negative and a positive regulator of ahyI and hence C4-HSL production in a growth phase dependent manner.
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PMID:The Aeromonas hydrophila LuxR homologue AhyR regulates the N-acyl homoserine lactone synthase, AhyI positively and negatively in a growth phase-dependent manner. 1555 17

Pseudomonas aeruginosa is a gram-negative bacterium that causes serious illnesses, particularly in immunocompromised individuals, often with a fatal outcome. The finding that the acylated homoserine lactone quorum sensing (QS) system controls the production of virulence factors in P. aeruginosa makes this system a possible target for antimicrobial therapy. It has been suggested that an N-(3-oxododecanoyl)-homoserine lactone (3O-C12-HSL) antagonist, a QS blocker (QSB), would interfere efficiently with the quorum sensing system in P. aeruginosa and thus reduce the virulence of this pathogen. In this work, a mathematical model of the QS system in P. aeruginosa has been developed. The model was used to virtually add 3O-C12-HSL antagonists that differed in their affinity for the receptor protein and for their ability to mediate degradation of the receptor. The model suggests that very small differences in these parameters for different 3O-C12-HSL antagonists can greatly affect the success of QSB based inhibition of the QS system in P. aeruginosa. Most importantly, it is proposed that the ability of the 3O-C12-HSL antagonist to mediate degradation of LasR is the core parameter for successful QSB based inhibition of the QS system in P. aeruginosa. Finally, this study demonstrates that QSBs can shift the system to a low steady state, corresponding to an uninduced state and thus, suggests that the use of 3O-C12-HSL antagonists may constitute a promising therapeutic approach against P. aeruginosa involved infections.
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PMID:Modeling the effect of acylated homoserine lactone antagonists in Pseudomonas aeruginosa. 1582 19

Burkholderia cenocepacia is an opportunistic human pathogen that can aggressively colonize the cystic fibrosis lung. This organism has a LuxR/LuxI-type quorum sensing system that enables cell-cell communication via exchange of acyl homoserine lactones (AHLs). The CepR and CepI proteins constitute a global regulatory system, controlling expression of at least 40 genes, including those controlling swarming motility and biofilm formation. In this study, we isolated seven lacZ fusions in a clinical isolate of B. cenocepacia that are inducible by octanoyl-HSL. Induction of all of these genes requires CepR. The cepI promoter was tested for induction by a set of 33 synthetic autoinducers and analogues, and was most strongly induced by long-chain AHLs lacking 3-oxo substitutions. Expression of this promoter was inhibited by high concentrations of three different autoinducers, each having six-carbon acyl chains. When CepR protein was overproduced in Escherichia coli, it accumulated in a soluble form in the presence of octanoyl-HSL, but accumulated only as insoluble inclusion bodies in its absence. Purified CepR-OHL complexes bound to specific DNA sequences at the cepI and aidA promoters with high specificity. These binding sites included a 16-nucleotide imperfect dyad symmetry. Both CepR binding sites are centred approximately 44 nucleotides upstream of the respective transcription start sites.
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PMID:Direct binding of the quorum sensing regulator CepR of Burkholderia cenocepacia to two target promoters in vitro. 1597 77

Quorum sensing (QS) in Sinorhizobium meliloti, the N-fixing bacterial symbiont of Medicago host plants, involves at least half a dozen different N-acyl homoserine lactone (AHL) signals and perhaps an equal number of AHL receptors. The accumulation of 55 proteins was found to be dependent on SinI, the AHL synthase, and/or on ExpR, one of the AHL receptors. Gas chromatography-mass spectrometry and electrospray ionization tandem mass spectrometry identified 3-oxo-C(14)-homoserine lactone (3-oxo-C(14)-HSL), C(16)-HSL, 3-oxo-C(16)-HSL, C(16:1)-HSL, and 3-oxo-C(16:1)-HSL as the sinI-dependent AHL QS signals accumulated by the 8530 expR(+) strain under the conditions used for proteome analysis. The 8530 expR(+) strain secretes additional, unidentified QS-active compounds. Addition of 200 nM C(14)-HSL or C(16:1)-HSL, two of the known SinI AHLs, affected the levels of 75% of the proteins, confirming that their accumulation is QS regulated. A number of the QS-regulated proteins have functions plausibly related to symbiotic interactions with the host, including ExpE6, IdhA, MocB, Gor, PckA, LeuC, and AglE. Seven of 10 single-crossover beta-glucuronidase (GUS) transcriptional reporters in genes corresponding to QS-regulated proteins showed significantly different activities in the sinI and expR mutant backgrounds and in response to added SinI AHLs. The sinI mutant and several of the single-crossover strains were significantly delayed in the ability to initiate nodules on the primary root of the host plant, Medicago truncatula, indicating that sinI-dependent QS regulation and QS-regulated proteins contribute importantly to the rate or efficiency of nodule initiation. The sinI and expR mutants were also defective in surface swarming motility. The sinI mutant was restored to normal swarming by 5 nM C(16:1)-HSL.
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PMID:sinI- and expR-dependent quorum sensing in Sinorhizobium meliloti. 1629 66

The three-dimensional structure of a complex between the N-terminal domain of the quorum sensing protein SdiA of Escherichia coli and a candidate autoinducer N-octanoyl-L-homoserine lactone (C8-HSL) has been calculated in solution from NMR data. The SdiA-HSL system shows the "folding switch" behavior that has been seen for quorum-sensing factors produced by other bacterial species. In the presence of C8-HSL, a significant proportion of the SdiA protein is produced in a folded, soluble form in an E.coli expression system, whereas in the absence of acyl homoserine lactones, the protein is expressed into insoluble inclusion bodies. In the three-dimensional structure, the autoinducer molecule is sequestered in a deep pocket in the hydrophobic core, forming an integral part of the core packing of the folded SdiA. The NMR spectra of the complex show that the bound C8-HSL is conformationally heterogeneous, either due to motion within the pocket or to heterogeneity of the bound structure. The C8-HSL conformation is defined by NOEs to the protein only at the terminal methyl group of the octanoyl chain. Unlike other well-studied bacterial quorum sensing systems such as LuxR of Vibrio fischeri and TraR of Agrobacterium tumefaciens, there is no endogenous autoinducer for SdiA in E.coli: the E.coli genome does not contain a gene analogous to the LuxI and TraI autoinducer synthetases. We show that two other homoserine lactone derivatives are also capable of acting as a folding-switch autoinducers for SdiA. The observed structural heterogeneity of the bound C8-HSL in the complex, together with the variety of autoinducer-type molecules that can apparently act as folding switches in this system, are consistent with the postulated biological function of the SdiA protein as a detector of the presence of other species of bacteria.
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PMID:Structure of the Escherichia coli quorum sensing protein SdiA: activation of the folding switch by acyl homoserine lactones. 1630 57


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