Bacillus subtilisLmrA Is a Repressor of thelmrABandyxaGHOperons: Identification of Its Binding Site and Functional Analysis oflmrBandyxaGH

Yoshida, Ken-ichi; Ohki, Yo-hei; Murata, M.; Kinehara, Masaki; Matsuoka, Hiroshi; Satomura, Takenori; Ohki, Reiko; Kumano, Miyuki; Yamane, Kunio; Fujita, Yuki

doi:10.1128/jb.186.17.5640-5648.2004

Cited by 27 publications

(32 citation statements)

References 26 publications

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“…Finally, the organization of breR with respect to breAB represents a novel arrangement for these systems, since the genes that encode TetR regulators that control the expression of the cognate genes encoding RND efflux systems are localized either in a divergent orientation adjacent to the genes they regulate (1,17,31,35) or in the same operon (39,53). In contrast, breR is located 8.99 kb upstream, positioned several genes away from the breAB operon.…”

Section: Discussionmentioning

confidence: 99%

The Bile Response Repressor BreR Regulates Expression of the Vibrio cholerae breAB Efflux System Operon

2008

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Enteric pathogens have developed several resistance mechanisms to survive the antimicrobial action of bile. We investigated the transcriptional profile of Vibrio cholerae O1 El Tor strain C6706 under virulence geneinducing conditions in the presence and absence of bile. Microarray analysis revealed that the expression of 119 genes was affected by bile. The mRNA levels of genes encoding proteins involved in transport were increased in the presence of bile, whereas the mRNA levels of genes encoding proteins involved in pathogenesis and chemotaxis were decreased. This study identified genes encoding transcriptional regulators from the TetR family (vexR and breR) and multidrug efflux pumps from the resistance-nodulation-cell division superfamily (vexB and vexD [herein renamed breB]) that were induced in response to bile. Further analysis regarding vexAB and breAB expression in the presence of various antimicrobial compounds established that vexAB was induced in the presence of bile, sodium dodecyl sulfate, or novobiocin and that the induction of breAB was specific to bile. BreR is a direct repressor of the breAB promoter and is able to regulate its own expression, as demonstrated by transcriptional and electrophoretic mobility shift assays (EMSA). The expression of breR and breAB is induced in the presence of the bile salts cholate, deoxycholate, and chenodeoxycholate, and EMSA showed that deoxycholate is able to abolish the formation of BreR-P breR complexes. We propose that deoxycholate is able to interact with BreR and induce a conformational change that interferes with the DNA binding ability of BreR, resulting in breAB and breR expression. These results provide new insight into a transcriptional regulator and a transport system that likely play essential roles in the ability of V. cholerae to resist the action of bile in the host.

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Section: Discussionmentioning

confidence: 99%

The Bile Response Repressor BreR Regulates Expression of the Vibrio cholerae breAB Efflux System Operon

2008

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“…Increased transcription also results in overexpression of the MDT. Puromycin-and lincomycin-resistant (PLR) mutants, isolated by growing B. subtilis 168 in the presence of high concentrations of puromycin and lincomycin, display increased expression of LmrB because of the inactivation of a negative transcriptional regulator, LmrA, or because of mutations in the 5Ј untranslated region (5Ј UTR), which is a binding site for the LmrA protein (16,25). Expression of Bmr and Blt is regulated by the product of adjacent genes encoding the transcriptional activators BmrR and BltR, respectively (1,2).…”

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Increased Stability ofbmr3mRNA Results in a Multidrug-Resistant Phenotype inBacillus subtilis

Ohki

Tateno

2004

J Bacteriol

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“…With the combination of DNA microarray analysis and genome-wide computational sequence analysis, another LmrA target, yxaGH, was identified, which was found in the putative yxaGH promoter region two tandem LmrA-binding cis sequences, each of which is similar to that in the lmrAB promoter region (30). However, the DNA binding of LmrA was not inhibited by lincomycin, with the inducer interacting with LmrA remaining to be identified (30). Besides these findings, it was reported that yxaG encodes quercetin 2,3-dioxygenase, which is involved in flavonol degradation (3), whereas yxaH encodes a membrane protein of unknown function.…”

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Dual Regulation of the Bacillus subtilis Regulon Comprising the lmrAB and yxaGH Operons and yxaF Gene by Two Transcriptional Repressors, LmrA and YxaF, in Response to Flavonoids

et al. 2007

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Bacillus subtilis LmrA is known to be a repressor that regulates the lmrAB and yxaGH operons; lmrB and yxaG encode a multidrug resistance pump and quercetin 2,3-dioxygenase, respectively. DNase I footprinting analysis revealed that LmrA and YxaF, which are paralogous to each other, bind specifically to almost the same cis sequences, LmrA/YxaF boxes, located in the promoter regions of the lmrAB operon, the yxaF gene, and the yxaGH operon for their repression and containing a consensus sequence of AWTATAtagaNYGgTCTA, where W, Y, and N stand for A or T, C or T, and any base, respectively (three-out-of-four match [in lowercase type]). Gel retardation analysis indicated that out of the eight flavonoids tested, quercetin, fisetin, and catechin are most inhibitory for LmrA to DNA binding, whereas quercetin, fisetin, tamarixetin, and galangin are most inhibitory for YxaF. Also, YxaF bound most tightly to the tandem LmrA/YxaF boxes in the yxaGH promoter region. The lacZ fusion experiments essentially supported the above-mentioned in vitro results, except that galangin did not activate the lmrAB and yxaGH promoters, probably due to its poor incorporation into cells. Thus, the LmrA/YxaF regulon presumably comprising the lmrAB operon, the yxaF gene, and the yxaGH operon is induced in response to certain flavonoids. The in vivo experiments to examine the regulation of the synthesis of the reporter β-galactosidase and quercetin 2,3-dioxgenase as well as that of multidrug resistance suggested that LmrA represses the lmrAB and yxaGH operons but that YxaF represses yxaGH more preferentially.

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Bacillus subtilisLmrA Is a Repressor of thelmrABandyxaGHOperons: Identification of Its Binding Site and Functional Analysis oflmrBandyxaGH

Cited by 27 publications

References 26 publications

The Bile Response Repressor BreR Regulates Expression of the Vibrio cholerae breAB Efflux System Operon

The Bile Response Repressor BreR Regulates Expression of the Vibrio cholerae breAB Efflux System Operon

Increased Stability ofbmr3mRNA Results in a Multidrug-Resistant Phenotype inBacillus subtilis

Dual Regulation of the Bacillus subtilis Regulon Comprising the lmrAB and yxaGH Operons and yxaF Gene by Two Transcriptional Repressors, LmrA and YxaF, in Response to Flavonoids

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