LmrR Is a Transcriptional Repressor of Expression of the Multidrug ABC Transporter LmrCD in
            <i>Lactococcus lactis</i>

Agustiandari, Herfita; Lubelski, Jacek; Saparoea, H. van den Berg van Bart; Kuipers, Oscar P.; Driessen, Arnold J. M.

doi:10.1128/jb.01151-07

Cited by 72 publications

(117 citation statements)

References 31 publications

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“…About 100 genes involved in cellular metabolism and morphology were found to be differentially expressed in the transcriptome of the cholate-adapted strain. This is in sharp contrast to what was observed in cholate-adapted wild-type L. lactis cells, which showed a prominent defect in the lmrR gene that encodes a transcriptional repressor of lmrCD expression, which resulted in the constitutive expression of the lmrCD genes (1,32). Interestingly, neither the well-characterized transporters LmrA and LmrP nor any of the other remaining putative MDR transporters were found to be upregulated in the cholateadapted ⌬LmrCD r strain, lending further support to the notion that bile acid extrusion is a key activity of LmrCD.…”

Section: Discussioncontrasting

confidence: 50%

“…Furthermore, the apparent lack of major extrusion activity in the ⌬LmrCD r cells suggests that LmrCD is the major contributor in cholate extrusion and lends further support for the notion that the cholate resistance of the ⌬LmrCD r strain is unrelated to a transport phenomenon. The expression of the lmrCD genes in L. lactis is controlled by the transcriptional regulator LmrR (1). Previous studies have demonstrated that binding of drugs like Hoechst 33342 and daunomycin to LmrR relieves the repression of the lmrCD genes, thus leading to the manifestation of the MDR phenotype.…”

Section: Resultsmentioning

confidence: 99%

“…Previously, we have demonstrated that L. lactis cells lacking the genes encoding the heterodimeric ABC-type MDR transporter LmrCD become about twofold more susceptible to cholate than wild-type cells (31). Transcriptome analysis of the MDR strain of L. lactis selected for cholate resistance showed, among other things, a marked induction of lmrCD expression (31) that could be related to inactivation of the transcriptional regulator LmrR (1). These data suggest an important role of LmrCD in resistance to cholate but do not exclude an involvement of other transporters or non-efflux-based mechanisms in cholate resistance.…”

Section: Resultsmentioning

confidence: 99%

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The ABC-Type Multidrug Resistance Transporter LmrCD Is Responsible for an Extrusion-Based Mechanism of Bile Acid Resistance in Lactococcus lactis

Zaidi¹,

Bakkes²,

Lubelski

et al. 2008

J Bacteriol

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Upon prolonged exposure to cholate and other toxic compounds, Lactococcus lactis develops a multidrug resistance phenotype that has been attributed to an elevated expression of the heterodimeric ABC-type multidrug transporter LmrCD. To investigate the molecular basis of bile acid resistance in L. lactis and to evaluate the contribution of efflux-based mechanisms in this process, the drug-sensitive L. lactis NZ9000 ⌬lmrCD strain was challenged with cholate. A resistant strain was obtained that, compared to the parental strain, showed (i) significantly improved resistance toward several bile acids but not to drugs, (ii) morphological changes, and (iii) an altered susceptibility to antimicrobial peptides. Transcriptome and transport analyses suggest that the acquired resistance is unrelated to elevated transport activity but, instead, results from a multitude of stress responses, changes to the cell envelope, and metabolic changes. In contrast, wild-type cells induce the expression of lmrCD upon exposure to cholate, whereupon the cholate is actively extruded from the cells. Together, these data suggest a central role for an efflux-based mechanism in bile acid resistance and implicate LmrCD as the main system responsible in L. lactis.

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Section: Discussioncontrasting

confidence: 50%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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The ABC-Type Multidrug Resistance Transporter LmrCD Is Responsible for an Extrusion-Based Mechanism of Bile Acid Resistance in Lactococcus lactis

Zaidi¹,

Bakkes²,

Lubelski

et al. 2008

J Bacteriol

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“…Prior to this study, the interaction of LmrR with the Hoechst 33342 drug was shown. LmrR, however, is a repressor belonging to the second subfamily of the PadR-like regulators with a short C-terminal domain (49). In contrast to VanR and LmrR, PadR could not be deactivated by the direct binding of phenolic acid as an effector (25).…”

Section: Discussionmentioning

confidence: 99%

Transcriptional Regulation of the Vanillate Utilization Genes ( vanABK Operon) of Corynebacterium glutamicum by VanR, a PadR-Like Repressor

et al. 2015

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P lant biomass is the main carbon supply in the soil. The plant cell wall is a lignocellulosic complex consisting of hydrophilic polymers, i.e., cellulose, hemicellulose, and pectin, along with the hydrophobic aromatic heteropolymer lignin (1, 2). The integrity of the plant cell wall depends on its lignin content, which is crosslinked to polysaccharides by hydroxycinnamic acids bridges, mainly ferulate (3-5). These feruloylated polysaccharides, especially the ferulate-arabinoxylan complex, serve as initiation sites for lignification in the cell walls (6, 7). Lignin is degraded by lignolytic enzymes, including lignin peroxidase, manganese peroxidase, or laccase, into ␤-aryl ether, di-aryl ether, and biphenyl, which are further catabolized to other aromatic compounds, such as vanillin and vanillate. Likewise, ferulate bound through ester linkages to hemicellulose is released by esterases and degrades to vanillin and vanillate (for a review, see references 4, 5, 8, 9, and 10).Phenolic acids released by degradation of lignin, e.g., ferulate or p-coumarate, are toxic for many Gram-positive bacteria, such as Bacillus subtilis, at low pH. Thus, there is a system for phenolic acid stress response which detoxifies phenolic acid by decarboxylation and generation of vinyl phenol derivatives (11). In contrast to B. subtilis, Corynebacterium glutamicum utilizes ferulate, vanillin, and vanillate derived from lignin degradation as a carbon source. Generally, aromatic compounds are channeled via gentisate, catechol, protocatechuate, 1,2,4-trihydroxybenzene, or phenylacetyl coenzyme A (phenylacetyl-CoA) intermediates into the central carbon metabolism of C. glutamicum (12). Ferulate is catabolized via vanillin and vanillate as the intermediate products to protocatechuate (3,4-dihydroxybenzoate) (see Fig. S1 in the supplemental material) (13). Protocatechuate is further metabolized in the aerobic ␤-ketoadipate pathway and finally flows into the carbon and energy cycle (14). So far, only the genes for degradation of vanillate are identified in C. glutamicum. Conversion of vanillate to protocatechuate is carried out by vanillate O-demethylase (see Fig. S1) (13). The vanillate O-demethylase enzyme has two subunits, which are encoded by vanA (NCgl2300) and vanB (NCgl2301) (13,15). In addition to vanillate O-demethylase, the vanillate utilization system consists of a vanillate transporter encoded by vanK (NCgl2302), which forms the vanABK operon along with vanA and vanB (16). Transcription of the vanABK operon is regulated by VanR (NCgl2299), which forms a divergon with the vanABK operon (12).VanR belongs to the PadR-like transcriptional regulator family (17). The PadR-like protein family (Pfam accession no. PF03551) contains 26 reported structures deposited in the Protein Data Bank (http://www.rcsb.org/). Generally, PadR-like regulators play an important role in their bacterial host, especially concerning virulence and stress. Structurally, PadR-type regulators contain a highly conserved N-terminal winged helix-turn-helix (wHTH)

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“…To date, the function is known for only a few members of the PadR family, which have been shown to play a major role in the biology of their host bacteria. Among these members, (i) AphA from Vibrio cholerae is a quorum sensingregulated activator that initiates the virulence cascade and is a repressor of penicillin amidase activity (pva gene) (18,19,20,23), (ii) LadR from Listeria monocytogenes negatively regulates the expression of the multidrug efflux pump MdrL (17), (iii) LstR is required for effective thermal resistance (35), and (iv) LmrR from Lactococcus lactis regulates the production of LmrCD, a major multidrug ABC transporter (1,25). Crystal structures of two PadR-like proteins, AphA (11) and Pex (5), revealed a protein structure containing a conserved N-terminal winged helix-turn-helix (WHTH) that acts as the DNA-binding motif (4).…”

mentioning

confidence: 99%

Genetic and Biochemical Analysis of PadR- padC Promoter Interactions during the Phenolic Acid Stress Response in Bacillus subtilis 168

Nguyen¹,

Tran

Cavin³

2011

J Bacteriol

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Bacillus subtilis 168 is resistant to phenolic acids by expression of an inducible enzyme, the phenolic acid decarboxylase (PadC), that decarboxylates these acids into less toxic vinyl derivatives. In the phenolic acid stress response (PASR), the repressor of padC, PadR, is inactivated by these acids. Inactivation of PadR is followed by a strong expression of padC. To elucidate the functional interaction between PadR and the padC promoter, we performed (i) footprinting assays to identify the region protected by PadR, (ii) electrophoretic mobility shift assays (EMSAs) with a modified padC promoter protected region to determine the interacting sequences, and (iii) random mutagenesis of padR to identify amino acid residues essential for the function of PadR. We identified an important consensus dyad sequence called IR1-2 (ATGT-8N-ACAT) overlapping a second dyad element (GTGT-8N-ACAT) that we named dIR1-2bis. The entire dIR1-2bis/IR1-2 sequence permits binding of two PadR dimers in EMSAs, which may be observed for bacteria grown under noninduced conditions where the padC promoter is completely repressed. Three groups of modified PadRs giving a PASR phenotype were characterized in vivo. The DNA sequences of certain mutant padR alleles indicate that important residues are all located in the region containing the coiled-coil leucine zipper domain that is involved in dimerization. These substitutions reduce the affinity of PadR binding to the padC promoter. Of particular interest are residue L128, located at the center of the putative coiled-coil leucine zipper domain, and residue E97, which is conserved among all PadRs.

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LmrR Is a Transcriptional Repressor of Expression of the Multidrug ABC Transporter LmrCD in Lactococcus lactis

Cited by 72 publications

References 31 publications

The ABC-Type Multidrug Resistance Transporter LmrCD Is Responsible for an Extrusion-Based Mechanism of Bile Acid Resistance in Lactococcus lactis

The ABC-Type Multidrug Resistance Transporter LmrCD Is Responsible for an Extrusion-Based Mechanism of Bile Acid Resistance in Lactococcus lactis

Transcriptional Regulation of the Vanillate Utilization Genes ( vanABK Operon) of Corynebacterium glutamicum by VanR, a PadR-Like Repressor

Genetic and Biochemical Analysis of PadR- padC Promoter Interactions during the Phenolic Acid Stress Response in Bacillus subtilis 168

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