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J Bacteriol. Jul 2007; 189(14): 5387–5392.
Published online May 11, 2007. doi:  10.1128/JB.00553-07
PMCID: PMC1951852

QseA and GrlR/GrlA Regulation of the Locus of Enterocyte Effacement Genes in Enterohemorrhagic Escherichia coli[down-pointing small open triangle]


Transcription of the locus of enterocyte effacement (LEE) genes in enterohemorrhagic Escherichia coli (EHEC) is regulated by the LEE-encoded Ler and GrlR/GrlA proteins as well as the non-LEE-encoded regulator QseA. This work demonstrates that GrlR/GrlA activate LEE2 transcription in a Ler-independent fashion, whereas transcription of grlRA is activated by QseA in both Ler-dependent and -independent manners.

Enterohemorrhagic Escherichia coli (EHEC) is a human pathogen that colonizes the large intestine and causes attaching and effacing (AE) lesions on intestinal epithelial cells. This pathogen is notorious for causing outbreaks of bloody diarrhea and hemolytic uremic syndrome throughout the world (2, 17, 40). EHEC O157:H7 and many other Shiga toxin-producing E. coli (STEC) strains share the ability to produce AE lesions with enteropathogenic E. coli (EPEC), rabbit enteropathogenic E. coli (REPEC), Citrobacter rodentium, and Hafnia alvei (38). These lesions efface the microvilli and rearrange the cytoskeleton to form their signature pedestal-like structure, which cups each bacterium (19, 22, 41). The genes responsible for the formation of AE lesions are located on a pathogenicity island named the locus of enterocyte effacement (LEE) (20). The LEE region contains 41 genes, the majority of which are organized into five major operons: LEE1, LEE2, LEE3, tir/LEE5, and LEE4 (7, 21, 26). These operons encode numerous proteins that include a type III secretion system involved in secretion of signals and intimate host cell interaction (18).

The LEE genes are regulated through the AI-3/epinephrine/norepinephrine quorum-sensing (QS) system, proposed to be involved in interkingdom communication between bacterium and host (38). Quorum signals activate transcription of the LEE genes through the QS E. coli regulator A (QseA) (34). QseA belongs to the family of LysR transcription factors, and qseA EHEC and EPEC mutants have a striking reduction in type III secretion and transcription of the LEE genes. In addition to activating transcription of the LEE genes through Ler, QseA autorepresses its own transcription (33, 34).

Regulation of the LEE genes is intricate and multifactorial. The LEE region contains a gene, ler (1, 4, 8, 10, 14, 21, 35), which encodes a protein that directly activates transcription of the LEE genes by counteracting H-NS repression (1, 4, 8, 14, 21, 35). Ler has been previously shown to activate transcription of the grlRA operon (1, 8). In addition, several other regulators have been implicated in the control of LEE genes at the transcriptional level, including Per (11, 21), GadX (30), H-NS (4, 14), hha (28), pch (16), IHF (44), and EtrA and EivF (45). Posttranscriptional regulation of the LEE genes has also been reported (24, 25).

In an effort to gain a comprehensive understanding of the LEE, a full set of deletion mutants for all 41 C. rodentium LEE genes was generated (6). These mutants were characterized for LEE gene expression, type III secretion, host actin modulation, and virulence in mice. This deletion analysis characterized open reading frames 10 and 11 within the LEE and renamed them grlA and grlR. GrlA is 23% identical to CaiF regulatory protein in Shigella flexneri (GenBank accession no. ABF02316.1), whereas GrlR is not significantly similar to peptides in any species other than homologs in the AE lesion-forming species. GrlA is highly conserved among all AE pathogens, namely, EPEC, EHEC, and C. rodentium (7). GrlA from both EPEC and EHEC can complement C. rodentium ΔgrlA (7). The GrlR/GrlA proteins have also been reported to interact with each other, adding yet another level of complexity to this regulatory network (5).

In a C. rodentium background, GrlR and GrlA have been previously described as both a repressor and an activator of LEE gene transcription, respectively, given that transcription of LEE1, LEE2, and LEE5 was diminished in a grlA mutant, while transcription of LEE1 was mildly elevated in a grlR mutant (6). It has also been reported that GrlA activates transcription of the C. rodentium LEE1 operon in both C. rodentium and E. coli K-12 backgrounds. These data suggested that the GrlA activation of C. rodentium LEE1 transcription does not require any additional C. rodentium-specific genes (1). The EHEC grlA gene can complement GrlA-dependent LEE1 transcription in C. rodentium. However, there are no reports on the mechanism by which GrlR/GrlA regulates transcription of the EHEC LEE1 operon. Upstream of the C. rodentium LEE1 operon there is an insertion sequence (IS) that is absent in EHEC, potentially resulting in the observed differences in regulation. Furthermore, discounting the presence of an IS element in the regulatory region of C. rodentium, the upstream region in the vicinity of the C. rodentium LEE1 promoter is not conserved between C. rodentium and EHEC (1) (Fig. (Fig.1).1). Barba et al. (1) published that GrlA activation of the C. rodentium LEE1 transcription required the upstream region adjacent to this promoter, which is not conserved in the EHEC LEE1 regulatory region, and is a very-low-complexity sequence (i.e., containing a large percentage of repeated nucleotides; Fig. Fig.1).1). Additionally, the EHEC LEE1 operon has two promoters, a distal promoter also found in EPEC and C. rodentium and a proximal promoter unique to EHEC (6, 21, 29, 34) (Fig. (Fig.1).1). To address the transcription of the EHEC LEE by GrlR/GrlA, we cloned the EHEC grlRA genes using primers Orf11R and Orf10Flac under the control of their own promoter in a low-copy-number vector, generating plasmid pRR18 (Tables (Tables11 and and2).2). This plasmid was then introduced into the E. coli K-12 strains containing chromosomal EHEC-derived LEE-lacZ transcriptional fusions TEVS232 (LEE1-lacZ), TEVS21 (LEE2-lacZ), TEVS26 (LEE3-lacZ), TEVS24 (LEE5-lacZ), and TEVS76 (LEE4-lacZ) and plated on 100-μg/ml ampicillin Luria-Bertani agar (LB) plates (Table (Table1).1). Given that the E. coli K-12 strain does not harbor ler, we were able to assess GrlR/GrlA-LEE-dependent regulation in the absence of Ler. We observed that during growth in LB, GrlR/GrlA strongly activated transcription of the LEE2 operon (30-fold) and yet had no effect on the other LEE operons, as measured by β-galactosidase activity (44) (Fig. (Fig.2A).2A). The reason for the differential regulation of the LEE2 operon in relation to the other LEE operons is unclear at this moment. One may hypothesize that high expression levels of LEE2 may aid in accumulating enough EscC to form the outer ring of the type three secretion system needle complex (23).

FIG. 1.
(A) Comparison between the LEE1 regulatory regions of C. rodentium and EHEC. Arrows correspond to mapped transcriptional start sites. (B) Alignment of the sequences of the LEE1 regulatory regions of EHEC, EPEC, and C. rodentium. Light gray shaded areas ...
FIG. 2.
(A) Ler-independent, GrlR/GrlA transcriptional regulation of the LEE genes. Plasmid pRR18 (grlRA genes) was introduced in K-12 strains containing chromosomal EHEC-derived LEE-lacZ transcriptional fusions TEVS232 (LEE1-lacZ), TEVS21 (LEE2-lacZ), TEVS26 ...
Strains and plasmids

Many reports describing the regulation of the LEE genes are from cultures grown in LB. However, there are other studies showing that the transcription of these genes is significantly higher in Dulbecco's modified Eagle's medium (DMEM), suggesting that the environmental signals sensed by the bacteria can alter gene expression (4, 36). In comparing culture conditions (vector-only controls), the basal-level transcription of LEE1 was up-regulated threefold in DMEM compared to LB (364 ± 10.7 Miller units in DMEM; 113 ± 4.3 Miller units in LB), and transcription of LEE2 (124.7 ± 10 Miller units in DMEM; 65 ± 7.1 Miller units in LB) and LEE3 (117 ± 9.8 Miller units in DMEM; 55.7 ± 3.5 Miller units in LB) was up-regulated twofold. The basal transcriptional levels of LEE4 and LEE5 were unchanged in either medium (Fig. (Fig.2A).2A). During growth in DMEM, transcription of LEE2 was also activated by GrlR/GrlA, but at a lower level than that in LB (6.5-fold in DMEM versus 30-fold in LB). In DMEM, GrlR/GrlA activated transcription of LEE4 twofold, in contrast to no activation in LB. We did not observe any effect on transcription of the LEE1, LEE3, and LEE5 operons in DMEM (Fig. (Fig.2A).2A). These results suggest that GrlR/GrlA can activate transcription of both LEE2 and LEE4 operons in a Ler-independent fashion and that the level of activation of these promoters is dependent on the growth conditions.

In order to uncouple the activity of GrlA and GlrR, we investigated the ability of GrlA and GrlR separately to regulate LEE gene transcription in E. coli K-12. We cloned the EHEC grlA gene under the control of an arabinose-inducible promoter, generating plasmid pRR17, and we cloned the EHEC grlR gene into pACYC177, generating plasmid pRR19 (Tables (Tables11 and and2).2). These plasmids were again introduced in the five E. coli K-12 strains containing chromosomal EHEC-derived LEE-lacZ transcriptional fusions described above and were plated on 50-μg/ml kanamycin plates. During growth in LB, neither GrlA nor GrlR alone had an effect on the transcription of any of the LEE operons (Fig. (Fig.2B2B and data not shown). These results suggest that Ler-independent GrlR/GrlA LEE2 transcriptional activation requires both proteins. Given that GrlA and GlrR have been previously shown to interact with each other (5), our results suggest that GrlA by itself is not able to activate transcription of LEE2.

In DMEM, GrlA expression caused a twofold repression of LEE2 transcription and a threefold repression of LEE3 transcription (Fig. (Fig.2C).2C). Transcription levels of LEE1, LEE4, and LEE5 were similar in the presence and absence of GrlA in DMEM. Transcription of all LEE operons was also not altered in DMEM in the presence of GrlR (Fig. (Fig.2D)2D) (there was a mild, less than twofold repression of LEE4). We observed differential LEE regulation by GrlA in different growth conditions, suggesting that GrlA may act in concert with other transcription factors to regulate transcription of the LEE genes and that these factors may not be expressed during growth in LB.

GrlA has been shown to activate transcription of the C. rodentium LEE1 in C. rodentium and E. coli K-12 backgrounds (1). However, transcription of the EHEC LEE1, although activated by GrlA in an EHEC background (15), is not activated by GrlA in an E. coli K-12 background (Fig. (Fig.2).2). These data indicate that EHEC LEE1 activation by GrlA is indirect and requires an additional transcription factor absent in E. coli K-12. The differential regulation of the EHEC and C. rodentium LEE1 transcription within a K-12 background might be explained by differences in the LEE1 regulatory region between these bacteria (Fig. (Fig.1).1). One candidate for being this EHEC transcription factor could be Ler itself. To test this hypothesis, we introduced the plasmid pSE1100 (21) containing ler into each of the newly generated pRR17 LEE-lacZ fusion strains (Tables (Tables11 and and2).2). Consistent with previous reports, transcription of LEE2, LEE3, and LEE5 was activated by Ler in both LB and DMEM (Fig. (Fig.2),2), while no regulation of LEE1 through Ler was observed (4, 8, 14, 21, 26, 39). Our results are in line with previous studies that demonstrate that Ler does not autoregulate its own transcription (4, 8, 14, 21, 26, 39), although one conflicting report suggests that Ler may autorepress its own expression (3). LEE4 transcription was activated by Ler twofold in LB and was not responsive to Ler in DMEM. This is also consistent with previous reports that transcription of LEE4 is not directly regulated by Ler in EHEC and is only mildly modulated by this protein in EPEC (21, 36).

The LEE2 and LEE3 operons have overlapping promoters (21, 35). Ler has been shown to directly bind (upstream of LEE2 and downstream of LEE3) to activate transcription of both operons (35). In the presence of both Ler and GrlA, transcription of LEE2 was enhanced in both LB and DMEM, suggesting that Ler and GrlA act cooperatively to activate LEE2 (Fig. (Fig.2).2). Conversely, transcription of LEE3 was repressed in the presence of Ler and GrlA, compared to its transcription in the presence of Ler alone. Nonetheless, in the presence of both regulators transcription of LEE3 was activated (Fig. (Fig.2).2). These results suggest that Ler and GrlA may have a negative relationship with each other with respect to the regulation of LEE3. One might speculate that the location of Ler binding sites in relation to these promoters (upstream of LEE2 and downstream of LEE3) might be responsible for the opposite relationship between GrlA and Ler in these regulatory regions.

Transcriptional regulation of the LEE region is a complex process involving multiple transcription factors (4, 21, 30, 34). An important environmental cue involved in LEE gene regulation is QS through the AI-3/epinephrine/norepinephrine signaling system. The presence of a functional luxS gene allows for efficient AI-3 production in EHEC in DMEM (42). To assess whether transcription of grlRA is part of the QS regulon, we introduced a plasmid containing a grlRA-lacZ transcriptional fusion in wild-type EHEC and several of its isogenic QS mutants, namely, ΔluxS and ΔqseA (Tables (Tables11 and and2).2). Transcription of grlRA was up-regulated 27-fold in a luxS mutant and restored to wild-type levels upon complementation of this mutation (Fig. (Fig.3A).3A). This suggests that a luxS mutation has the opposite effect on the transcription of grlRA than it has on the transcription of ler (38). However, LuxS has several functions besides autoinducer production within the cell. LuxS is a central metabolism enzyme that cleaves S-ribosylhomocysteine into homocysteine and 4,5-dihydroxy-2,3-pentanedione (DPD), which is the precursor of the AI-2 autoinducer (27). The metabolic alterations caused by a luxS mutation in EHEC also affect production of AI-3 (42). To test whether the effect of the luxS mutation on the expression of grlRA was due to QS or to the metabolic shift in the mutant, we assessed grlRA expression in the luxS mutant in the presence of the AI-2 and epinephrine (which can substitute for the AI-3 signal [38]) signals (Fig. (Fig.3C).3C). Neither one of these signals restored transcription to wild-type levels, suggesting that the effect of the luxS mutation on grlRA expression is due to the metabolic shift this mutation causes and not to QS.

FIG. 3.
(A) QseA- and LuxS-dependent regulation of grlRA in an EHEC background. Plasmid pVS255 (grlRA-lacZ) was transformed into host strains 86-24 (wild-type EHEC), VS94 (86-24 isogenic luxS mutant), VS95 (VS94 luxS complemented) (37), VS145 (86-24 isogenic ...

Transcription of grlRA was down-regulated twofold in a qseA mutant and up-regulated sixfold upon complementation of this mutation (Fig. (Fig.3A),3A), indicating that QseA is involved in activating transcription of this operon. Given that QseA activates transcription of ler (LEE1) (34) and Ler activates transcription of grlRA (8), we decided to address whether this activation occurred in a Ler-dependent manner. We then introduced the grlRA-lacZ fusion into E. coli K-12 strain MC4100, its isogenic qseA mutant, and complemented strains, and we observed that transcription of grlRA was decreased sixfold in the qseA mutant compared to that of the wild type and was rescued upon complementation (Fig. (Fig.3B).3B). These results suggest that QseA activation of grlRA transcription also occurs in two levels: first, by QseA activation of ler and with Ler-dependent subsequent activation of grlRA (1, 8) in a cascade fashion, and second, through QseA activation independent of Ler (Fig. (Fig.3).3). We have determined that grlRA activation by QseA is most likely not direct, given that electrophoretic mobility shift assays with purified QseA demonstrated that this protein does not bind directly to the grlRA regulatory region (unpublished data). The opposite phenotypes on grlRA transcription between the luxS (repression of grlRA transcription) and qseA (activation of grlRA transcription) mutants (Fig. (Fig.3)3) are not unexpected. QseA is one of several transcriptional regulators in this cascade, and LuxS has multiple functions within these cells; it is involved in the synthesis of QS signals and in central metabolism (27, 43).

Together, the present data allowed us to suggest an updated model of LEE gene regulation (Fig. (Fig.4).4). QseA directly activates transcription of ler (29), which then activates transcription of the remaining LEE genes, including grlRA. It has been shown through electrophoretic mobility shift assays that Ler directly activates transcription of grlRA, LEE2, LEE3, and LEE5 (1, 14, 39). Transcription of grlRA, however, is also indirectly activated by QseA in a Ler-independent manner, and QseA autorepresses its own expression (33). GrlR/GrlA, through an unidentified EHEC-specific transcription factor, modulates the transcription of LEE1 (6). In addition, GrlR/GrlA activates transcription of LEE2 and LEE4 in a Ler-independent manner (Fig. (Fig.4).4). Aside from regulation of the LEE genes, GrlR/GrlA also regulates transcription of at least six non-LEE-encoded effectors (6). Finally, QseA regulation of the grlRA genes indicates that this transcription factor is also regulating transcription of non-LEE-encoded effectors, further integrating LEE gene expression and effector translocation to epithelial cells.

FIG. 4.
Model of LEE gene regulation by QseA, Ler, and GrlR/GrlA. QseA activates transcription of ler, and Ler then activates transcription of the other LEE genes, including grlRA. Transcription of grlRA is also activated by QseA in a Ler-independent manner. ...


This research was supported by NIH grants AI054468 and AI053067 and the Ellison Medical Foundation.


[down-pointing small open triangle]Published ahead of print on 11 May 2007.


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