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Journal of Bacteriology, March 2008, p. 2239-2243, Vol. 190, No. 6
0021-9193/08/$08.00+0     doi:10.1128/JB.01826-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

SarA of Staphylococcus aureus Binds to the sarA Promoter To Regulate Gene Expression

Ambrose L. Cheung,^1* Koren Nishina, and Adhar C. Manna²

Department of Microbiology and Immunology, Dartmouth Medical School, Hanover, New Hampshire 03755,¹ Division of Basic Biomedical Sciences, Sanford School of Medicine, University of South Dakota, Vermillion, South Dakota 57069²

Received 19 November 2007/ Accepted 24 December 2007

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The 375-bp sarA open reading frame is driven by three promoters, P1, P3, and P2. Using gel shift and DNase I footprinting assays, we found that SarA binds to two 26-bp sequences and one 31-bp sequence within the P1 and P3 promoters, respectively. Together with the results of transcription analyses, our data indicate that SarA binds to its own promoter to down-regulate sarA expression.

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Staphylococcus aureus is an important human pathogen that can cause a wide spectrum of infections ranging from superficial abscesses to deep-seated infections such as pneumonia, endocarditis, and sepsis (14). This versatility may be attributable to an extensive array of extracellular and cell wall-associated virulence determinants that are coordinately expressed during the infection process (4, 19). The temporal regulation of virulence determinants in S. aureus has been shown to be under the control of global regulators such as agr and SarA (4, 19). SarA is a 14.5-kDa DNA binding protein that modulates the transcription of specific regulatory loci such as agr as well as downstream target genes (e.g., hla and spa). These two modes of regulation have been confirmed by transcriptional profiling studies by Dunman et al. (9). Recognizing that SarA can control over 120 genes both directly and indirectly (9), it is not surprising that expression of sarA is carefully controlled during bacterial growth (16).

The sarA promoter region is extensive at 800 bp in length, with three distinct promoters (P2, P3, and P1) that yield three overlapping transcripts (sarA P2, P3, and P1 transcripts). The sarA P1 and P2 promoters are ^A dependent, while the P3 promoter, nested between the P1 and P2 promoters (Fig. 1A), is ^B dependent (17) and is activated postexponentially or during period of metabolic stress (1). Promoter analysis using XylE fusions revealed that the sarA P1 promoter is the predominant promoter whereas the P2 and P3 promoters are much weaker (15). Mutation studies indicated that the weaker P2 and P3 promoters contributed to overall SarA expression, since activation of the P1 promoter alone led to lower SarA protein expression compared with expression levels seen with the native P2-P3-P1 promoters, thus resulting in reduced target gene expression (e.g., agr and hla) (6). Embedded within the sarA promoter regions are both direct and indirect repeats (1), suggesting that the promoter region may serve to provide binding sites for regulatory DNA binding proteins. Indeed, promoter trap studies have determined that SarR, a homolog of SarA, binds to the sarA P1 promoter to repress SarA expression (16) while SigB binds to the sarA P3 promoter (17). Thus, SigB (6, 17) and SarR (16) can affect the sarA P3 and P1 promoters, respectively, to modulate SarA expression during growth (16).

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FIG. 1. Binding of SarA to the sarA promoters. (A) The structure of the sarA locus, showing the triple promoter driving the sarA ORF. The nucleotide positions of the transcription starts (upstream of the sarA ATG initiation codon) are shown for the three promoters. (B) Gel shift of purified SarA with the -32P-labeled sarA P1 (nt 620 to 859) and P3 (nt 364 to 525) promoters (based on sequence data from GenBank accession number U46541). Lane 1 represents the labeled DNA probe alone. Increasing amounts of SarA at 0.2, 0.5, 1, and 3 µg, representing 6.8, 17, 34, and 102 pmol, respectively, were added to the probe (lanes 2 to 5). Unlabeled 240-bp P1 sarA or 162-bp sarA P3 (lane 6) in a 25-molar-ratio excess was added to a lane containing 3 µg of the purified SarA protein as a specific competitor, while an 185-bp mgrA promoter fragment with a 33-molar-ratio excess was also added to 3 µg of SarA (lane 7).

Besides SigB and SarR, we have now dissected the contribution of SarA to expression from its own promoter. Our data confirmed the negative regulatory role of SarA in reducing overall expression from the native sarA triple promoters.

Characterization of SarA binding to the native sarA promoter. Various studies have shown that SigB and SarR are involved in the modulation of SarA expression (Fig. 1A) (2, 5, 10, 16). Cognizant of the relatively minor role of the P2 promoter in sarA expression (6), we proceeded to ascertain whether SarA binds to the P3 and P1 promoters. Promoter fragments were amplified by PCR, gel purified, end labeled, and used in gel shift assays with purified SarA protein. Purification, authenticity, and purity of the purified His₆-tagged SarA protein were reported previously (8, 13). As shown in Fig. 1B, purified SarA protein bound to the P1 and P3 promoters in a dose-dependent fashion. We estimated that the dissociation constants of SarA with respect to the sarA P1 and P3 promoters are 17 and 34 pM, respectively. The onefold difference in dissociation constants for SarA between the two sarA promoters is not highly significant and is probably within the experimental error of the gel shift assays. Unlabeled promoter DNA, added in excess (25-fold in molar ratio), was found to reduce the formation of the protein-DNA complex, thus suggesting binding specificity. In contrast to the results seen with the unlabeled sarA P3 promoter fragment (Fig. 1B, right panel, lane 6), the reduction in the formation of the protein-DNA complex for the unlabeled sarA P1 promoter was only partial (Fig. 1B, left panel, lane 6) in the presence of 3 µg of SarA (the same amount as used for lane 5). As a negative control, we used a 185-bp mgrA promoter fragment (in a 33-fold molar ratio) which did not compete as successfully as the unlabeled sarA P1 promoter fragment for the binding of SarA (Fig. 1B, left panel, lane 7). The presence of multiple retarded species would suggest the presence of a single binding site with multiple SarA dimers (13); however, we cannot rule out the possibility of multiple binding sites within this 240-bp sarA P1 promoter fragment.

The contribution of the sarA P2 to SarA expression has been shown to be relatively minor compared to that of the P3 and P1 promoters (5, 15). For this reason, we decided to analyze the binding site of SarA on the sarA P3 and P1 promoter regions by DNase I footprinting assays. We employed a -³²P-labeled 162-bp sarA promoter fragment (nucleotides [nt] 364 to 525) (GenBank accession no. U46541) upstream of P1 that also comprises the sarA P3 promoter region. As shown in Fig. 2A, protection from DNase I digestion of the sense strand with SarA was mapped to a 31-bp sequence with positions 389 to 419 (based on GenBank accession no. U46541) (1), approximately seven nucleotides upstream of the –35 promoter box of the P3 promoter. Additional mapping of the nonsense strand with SarA also confirmed this binding site (data not shown). Interestingly, there is a 7-bp palindrome separated by a 6-bp sequence within the protected region. This configuration is consistent with the presence of a binding site of a dimeric winged helix protein (11), and SarA belongs to the winged helix protein family (13). The partially protected region below nt 388 was likely due to nonspecific binding, since this protection was only observed at the highest SarA concentration and was not found in the footprinting assay with the nonsense strand (data not shown). Alignment of this sequence with the consensus SarA binding site (8) disclosed the identities of 15 of 26 residues (Fig. 2B). Notably, the consensus SarA binding site also contains an imperfect 7-bp inverted repeat which may serve as a binding site for winged helix proteins (11). Collectively, these studies confirmed the existence of a SarA binding site upstream of the P3 promoter.

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FIG. 2. (A) DNase I footprint of the sarA promoter (positions 364 to 525, covering the P3 promoter and part of the P1 promoter) with 1, 2, 3, and 0 µg of purified SarA added. Lane M represents an A/G ladder. (B) Alignment of the protected region (nt position 389 to 419) with the SarA consensus binding sequence derived from an alignment of all the promoter sequences to which SarA binds (8). For the consensus sequence, the capital letters represent highly conserved bases while the lowercase letters represent variable positions. Numbers are from data obtained from GenBank accession number U46541. Please note that the P3 protected region has a 7-bp palindrome (underlined) separated by a 6-bp sequence; this configuration is consistent with the binding site for a dimeric winged helix protein such as SarA (11, 13). Interestingly, the SarA consensus binding site encompasses an imperfect inverted repeat (double underlined), which may also serve as a binding site for winged helix proteins (11).

Effect on SarA on the P1 promoter. In contrast to the results seen with the sarA P3 promoter, we were not able to obtain a good SarA footprint on the sarA P1 promoter despite similar binding affinities of SarA with sarA P1 and sarA P3 promoters. In examining the sarA promoter region, we found two SarA consensus binding sites of 26 bp each (sarA P1-I and sarA P1-II; Fig. 3A) (8), one overlapping with the –10 promoter boxes and another downstream of the transcription start site. To verify the specificity of these two 26-bp binding sites, two 78-mers, each representing the binding site (i.e., sarA P1-I and sarA P1-II), together with the native 26-bp flanking sequence on each side, were synthesized and used for gel shift studies with purified SarA (Fig. 3B). We also used a nonspecific 78-bp competitor as a control for each gel; this fragment was similar to the specific competitor except that the central 26-bp sequence (26-bp sarA P1-I or 26-bp sarA P1-II) was replaced by GAC repeats. The results showed that these two native 78-bp fragments formed retarded species indicative of protein-DNA complex formation. The binding was likely to be specific, because the unlabeled 78-bp fragment competed successfully for the complex (Fig. 3B) whereas the 78-bp nonspecific competitor fragment was less successful (Fig. 3B). Interestingly, the nonspecific competitor for the sarA P1-I fragment formed two complexes, one specific and another nonspecific (3B). Progressive retardation of the complexes with increasing concentrations of SarA suggests that the protein likely forms multiple dimers on target DNA, since modeling studies of the SarA protein with promoter DNA revealed the plausibility of the idea that three SarA dimers bind to the target promoter (13). Additionally, multiple SarA-DNA complexes were also discerned when we used a 26-bp fragment, comprising only the binding site, in place of the 78-bp fragment for the gel shift assay. Given that a 26-bp sequence is probably too short to accommodate multiple binding sites for multiple SarA dimers, we theorize that the SarA dimers likely bind to a single site via dimer-dimer interaction (13).

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FIG. 3. The binding of SarA to two separate SarA binding sites in the sarA P1 promoter region. (A) Sequence of the region, with the –10 and –35 of the P1 promoter boxes represented by boldface characters. The putative SarA binding sites (sarA P1-I and sarA P1-II) are indicated by dashes below the sequence; the sarA P1-II is located in the complementary strand. The transcription start site of the P1 transcript is indicated by a downward-pointing arrowhead. The alignment of the putative SarA binding sites with the SarA consensus sequence is shown. (B) Gel shift studies of the two binding sites with purified SarA. The wild-type oligonucleotides of sarA P1-I and P1-II are 78-mers, each consisting of the respective binding region (26 bases underlined in panel A) flanked by 26 bases of native sequence on each side. The wild-type oligonucleotides were biotinylated and exposed to various quantities of purified SarA protein under the following binding conditions: a total of 20 µl consisting of 2x binding buffer (Pierce Chemicals), 5% glycerol, 0.5 µg herring sperm DNA, 0.05% NP-40, 20 fmol of labeled oligonucleotides, and different concentrations of SarA protein. Detection of the bands was performed using a Pierce LightShift chemiluminescent electrophoretic mobility shift assay kit (Pierce Chemicals, Rockford, IL). The specific competitor was the unlabeled 78-bp oligonucleotide, while the nonspecific competitor was also 78 bp in length and was similar to the specific competitor except that the 26-bp binding sequence of sarA P1-I or sarA P1-II was replaced with GAC repeats while leaving the flanking sequences intact. The "A" in the label "100 + A" represents 50 pmol of the nonspecific competitor; the "B" in the label "100 + B" represents 50 pmol of the unlabeled 78-bp sarA P1-I or sarA P1-II fragment as the specific competitor (as indicated in the figure panel). The specific complexes are indicated by short arrows, while the long arrow highlights the nonspecific complex.

To confirm the effect of SarA on the sarA P1 and P3 promoters, we transformed shuttle plasmid (pSK236) containing the intact P2-P3-P1 promoters into wild-type strain Newman and its isogenic sarA mutant. Strain Newman was chosen because it contains an intact rsbU gene, which represents part of a regulatory input into the sigB operon to generate free SigB under conditions of environmental stresses (20). This is relevant within the context of the SigB dependency of the sarA P3 promoter. To improve signal detection, we elected to examine transcription of gfp linked to the sarA promoter to ascertain sarA promoter activity, since this would avoid the problem of protein degradation associated with many reporter fusions (e.g., XylE, β-galactosidase) (3, 6, 15). In strain Newman, the level of sarA P3 transcription from the sarA P2P3P1:gfp construct was lower in the parent than that in the isogenic sarA mutant (no detectable units versus 1,340 units in lanes 1 and 2 and 1,002 versus 2,342 units in lanes 3 and 4 for the exponential and postexponential phases, respectively), thus implying a repressive effect by SarA on the P3 promoter (Fig. 4). The sarA P1 promoter within the native P2-P3-P1 promoters was also more active in the sarA mutant (i.e., in the absence of SarA) than in the parental counterpart Newman (Fig. 4A, lane 2 versus lane 1 and lane 4 versus lane 3). Although our data did not entirely rule out the contributory role of SarA binding to the P2 promoter to alter P1 transcription, the fact that the P2 promoter is very weak (15) and also quite distal to P1 (the two promoters are 560 bp apart) would suggest minimal influence of the P2 promoter on the proximal P1 promoter (Fig. 1A).

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FIG. 4. (A) Northern blots of the sarA promoters linked to gfp as detected by a gfp probe, by use of the coding region of gfp, in strain Newman and its isogenic sarA mutant. By means of an 18-mm (outer diameter) borosilicate glass tube, RNA was harvested from strain Newman or its isogenic sarA mutant at ODs at 650 nm (OD650) of 0.7 and 1.7, corresponding to the exponential and postexponential phases, respectively. Equivalent amounts of total cellular RNA were resolved in denaturing agarose gel, blotted onto a Hybond XL membrane (GE Healthcare), and hybridized with a [32P]dCTP-labeled gfp probe as described previously (16). The results of densitometric analyses of signal intensities for the P1 and P3 transcripts, performed using Sigma Gel software from Jandel Scientific, are indicated below the lanes. ND, result was below the minimum level that can be detected with the Sigma Gel software. (B) Promoter fusions of sarA P2-P3-P1 promoters driving the gfpuvr reporter gene in isogenic sarA Newman strains. S. aureus strains containing recombinant shuttle plasmid with the sarA P2-P3-P1 promoters driving the GFPuvr-encoding gene were grown in tryptic soy broth overnight, diluted 1:100, and then serially monitored for OD650 and fluorescence in microtiter wells (FL600; Biotek, Winooski, VT). About 100 µl each of the samples was added in triplicate to each microtiter well. The data are presented as the numbers of mean fluorescence units/OD in the y axis versus time in hours after the initial dilution in the x axis. The standard error of the mean was too small to be seen for each data point in the graph.

To confirm the effect of SarA on the native sarA P2-P3-P1 promoters in overall sarA expression, we conducted transcription fusion experiments using the native sarA promoter linked to the GFP_uvr reporter gene in strain Newman and its isogenic sarA mutant. As shown in Fig. 4B, the transcription of the intact sarA P2-P3-P1 promoters, as confirmed by the level of green fluorescent protein (GFP)-mediated fluorescence per optical density (OD) unit, was higher in the sarA mutant than in the isogenic parental strain Newman throughout the growth cycle. This confirms our Northern blot data (Fig. 4A) showing that expression of the sarA P1 and P3 promoters is repressed by SarA and is derepressed in the sarA mutant.

The sarA promoter region of S. aureus is complex, with three promoters (P2, P3, and P1) in an extensive region (800 bp). Transcriptional analysis revealed that the P1 promoter is most active whereas the sigB-dependent P3 promoter also contributes to sarA expression (5, 6, 15). Surprisingly, the distal P2 promoter is weak in vitro and in vivo and appears to play a relatively minor role in driving SarA expression (6, 7). We have previously speculated that the region between the P1 and P3 promoters may serve to provide binding sites for regulatory proteins based on the observation that there are both direct and inverted repeats in this region. Indeed, we have subsequently found that SigB and SarR can bind to the sarA promoter to activate the P3 promoter and repress the P1 promoter, respectively (Fig. 1) (5, 16). As the sarA locus controls over 120 target genes (9), we hypothesize that additional activators or repressors are likely to be present to modulate SarA expression.

In previous sarA promoter fusion studies using XylE and GFP in isogenic sarA strains (RN6390), we have found inconsistent results with respect to modulation of the sarA promoter by SarA (unpublished data). One of the reasons for this inconsistency may have been the presence of reduced SigB expression in strain RN6390, which leads to a partial failure in activating the ^B-dependent sarA P3 promoter. Another plausible reason is that we have previously looked at the sarA P3 or P1 promoter activation in isolation but not in the context of the native P2-P3-P1 promoters. To resolve this inconsistency, we decided to examine the effect of SarA on gfp transcription from P1 and P3 as driven from the native sarA P2-P3-P1 promoters in strain Newman, which carries an intact sigB operon with a functional rsbU gene. Based on our transcription and fluorescence data (Fig. 4A and 4B), we established that SarA is a negative regulator of overall sarA expression by virtue of its repressive effect on the P1 and P3 promoters, which play an important role in driving SarA expression from the native sarA P2-P3-P1 promoters (6, 15). This was confirmed by our transcriptional fusion data showing that the native sarA promoter was more active in driving GFP_uvr expression in the sarA mutant than in the parent strain (Fig. 4B). This effect was unlikely to be due to reduced expression of proteases, since a sarA mutant is expected to produce more proteases than the parent (4). Gel shift studies revealed that SarA can bind to the sarA P3 and P1 promoters. Curiously, we were able to obtain a good DNase I footprint with the sarA P3 promoter alone but not with the P1 promoter alone even though SarA seems to bind with similar levels of affinity to these two promoters, as indicated by the comparable amounts of SarA protein required for a complete shift of the labeled probe in gel shift assays. The SarA binding site on the sarA P3 promoter lies immediately upstream of the –35 promoter box. This 26-bp binding site shares homology with the 26-bp SarA binding site that we have mapped for the agr, hla, and other target promoters (8, 23). Additionally, this site also contains a 7-bp palindrome separated by a 6-bp sequence within the SarA protected region. Given that dimeric winged helix proteins typically bind to inverted repeats or palindromic sequences (11), it is highly likely that SarA, as a member of the winged helix family, binds specifically to this site.

In examining the sarA P1 promoter region, we found two 26-bp SarA consensus sequences, one overlapping with the –10 promoter box and another downstream of the transcription start site. Using these two sequences (sarA P1-I and P1-II) together with flanking sequence as 78-bp probe fragments, we showed that SarA could bind these two fragments specifically in a dose-dependent fashion, with the unlabeled native 78-bp sequence being a better competitor than the nonspecific 78-bp competitor in which the 26-bp SarA binding site had been replaced by GAC repeats (Fig. 3). We also conducted gel shift assays of purified SarA with only the 26-bp SarA binding sites (sarA P1-I and P1-II) lacking any flanking sequence, obtaining essentially similar results (unpublished data). Two interesting themes emerged from these binding studies. First, there were three protein-DNA complex species for each 26-bp sequence, thus hinting at multiple dimer interactions on a single binding site, as has been predicted from the structural studies of SarA (13). Second, the second SarA binding site lies downstream of the transcription start site of the sarA P1 transcript. This scenario has also been described for Rns, a global regulator of pilus expression in enterotoxigenic Escherichia coli which binds to a region downstream of the transcription initiation site to activate transcription from its own promoter (18).

Cognizant of our recent structural data showing that SarA is a dimeric winged helix protein (13), it is likely the binding site of SarA is greater than 17 bp in size and contains either a palindrome or an inverted repeat (based on our unpublished gel shift data with various sizes of the duplex DNA fragments and purified SarA protein), which is typical of most winged helix proteins with two winged helix motifs (e.g., OhrR, MecI, and BlaI), with each motif capable of binding to the major groove and minor groove of target DNA (11, 12, 21, 22). Accordingly, the data presented here are consistent with a larger binding site for two winged helix motifs.

In sum, our data support the idea of a complex regulatory structure within the triple sarA promoter to control SarA expression. In previous studies, we delineated the role of SigB and SarR in modulating SarA expression. We have now added SarA to this list of regulatory proteins. Similar to SarR, SarA also exerts a negative regulatory effect on the P1 and P3 promoters to down-modulate transcription from the native sarA P2-P3-P1 promoters to influence SarA expression. Delineation of other factors that may have positive regulatory input with respect to this promoter is currently in progress.

 
This research was supported in part by National Institutes of Health grant AI37142 to A.L.C.

 
* Corresponding author. Mailing address: Department of Microbiology and Immunology, Vail 210, Dartmouth Medical School, Hanover, NH 03766. Phone: (603) 650-1340. Fax: (603) 650-1362. E-mail: Ambrose.Cheung{at}Dartmouth.edu

Published ahead of print on 4 January 2008.

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Journal of Bacteriology, March 2008, p. 2239-2243, Vol. 190, No. 6
0021-9193/08/$08.00+0     doi:10.1128/JB.01826-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

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