L. monocytogenes possesses eight ATP binding cassette (ABC) transporters for carbohydrates. They are usually composed of a sugar binding protein anchored at the outside of the cytoplasmic membrane and two membrane-spanning permeases. In L. monocytogenes, most operons encoding carbohydrate-specific ABC transporters lack the gene for the ATP-hydrolyzing protein. Instead they use Lmo0278, which similar to MsmX in B. subtilis functions with most listerial sugar-transporting ABC systems. Lmo0278 probably interacts with the cytoplasmic loops of the membrane-spanning components of seven listerial ABC systems transporting carbohydrates [81]. Only the ABC transporter encoded by Lmo0808-0810 possesses its own ATP-hydrolyzing protein Lmo0807.
Maltose and maltodextrose have been shown to be taken up by L. monocytogenes via the ABC transport system composed of Lmo2123, Lmo2124 and Lmo2125, which exhibit strong similarity to the L. casei membrane-spanning MalG and MalF proteins and the maltose-binding protein MalE, respectively [82, 83]. The operon lacks a gene for the ATP hydrolyzing enzyme MalK and the above mentioned Lmo0278 was shown to function as ATPase during maltose and maltodextrose uptake. The maltose operon contains three additional genes encoding enzymes resembling maltogenic amylase (Lmo2126), the maltodextrose utilization protein MalA (Lmo2122), and maltose phosphorylase (Lmo2121). The results published in [84] suggested that the ABC transporter would be the only uptake system for maltose present in L. monocytogenes. Surprisingly, when carrying out a fermentation test with the L.
monocytogenes wild type strain EGD-e and a ptsI deletion mutant derived from it (the latter lacks EI) we observed that the ptsI mutant had lost the capacity to ferment maltose (E.
Milohanic and J. Deutscher, unpublished results). However, we could not detect a L.
monocytogenes gene encoding a protein resembling either B. subtilis 6-P--glucosidase [85], which hydrolyzes maltose-6‘-P formed during PTS uptake, or E. faecalis maltose-6‘-P phosphatase, which dephosphorylates maltose-6‘-P [86] thus allowing the subsequent phosphorolysis of maltose to glucose and glucose-1-P. One possible explanation for the loss of maltose fermentation in the ptsI mutant might be that the absence of EI indirectly affects maltose uptake. The presence of glucose was found to inhibit maltose uptake by L.
monocytogenes, probably by an inducer exclusion mechanism. Similar as in L. casei [83, 87]
the inhibitory effect of glucose is apparently mediated via P-Ser-HPr, because in a L.
monocytogenes hprK mutant maltose uptake was no longer inhibited by the presence of glucose [84]. A mutant lacking EI most likely contains elevated amounts of P-Ser-HPr because it cannot form P~His-HPr, which probably represents the major fraction of the different HPr forms in the maltose-utilizing wild-type strain. In the ptsI mutant, part of the P~His-HPr fraction is converted into P-Ser-HPr, which might be sufficient to inhibit maltose uptake via the ABC transport system.
The other seven ABC transport systems of L. monocytogenes have not been studied and their substrate specificity is unknown. Nevertheless, based on the activity of the catabolic enzymes usually also encoded by the ABC transporter operons substrate specificities can be predicted. Most of them seem to transport disaccharides or longer oligosaccharides. For example, the ABC transporter encoded by lmo2839-2837 might transport maltitol, a polyol produced by plants and composed of a glucose and a glucitol moiety connected via an -1,4- glycosidic linkage (4-O--D-glucopyranosyl-D-glucitol). The presumed maltitol operon contains also the genes encoding proteins resembling maltose phosphorylase (Lmo2833), which might transform intracellular maltitol into glucose-1-P and glucitol. The resulting glucose-1-P is subsequently converted into glucose-6-P by one of the phosphoglucomutases present in L. monocytogenes. Glucitol might be oxidized to fructose by the oxidoreductase Lmo2834 or the alcohol dehydrogenase Lmo2836. A kinase of the glycerate kinase family, which might phosphorylate fructose to fructose-6-P, is encoded by Lmo2832. Two proteins presumed to exhibit oxidoreductase and cellobiose phosphorylase activity are also present upstream from the genes lmo1730-1732, which encode another sugar ABC transport system.
It is tempting to assume that Lmo1730-1732 might transport cellobiitol, which similar to maltitol is also composed of glucose and glucitol, with the only difference that maltitol contains an - and cellobiitol a -glucosidic linkage (4-O--D-glucopyranosyl-D-glucitol).
Cellobiitol is probably degraded via a pathway similar to that proposed for maltitol including its phosphorolysis to glucose-1-P and glucitol and the subsequent oxidation of glucitol to fructose.
The operon lmo0766-0769 encodes an ABC transporter and an enzyme resembling -1,6-mannanases, suggesting that this system, which lacks a sugar binding subunit, transports oligo-mannosides derived from mannanes present in plants. Lmo0179-0181 is likely to transport the degradation products of branched-chain oligosaccharides, because the presumed operon also encodes enzymes resembling -1,4- and -1,6- xylosidases and glucosidases.
Degradation products of a branched-chain polysaccharide might also be transported by the Lmo2009-2007 ABC transporter, because the presumed operon contains a gene encoding a protein resembling the membrane-embedded enzyme catalyzing the degradation of the complex polysaccharide rhamnogalacturonan. Lmo0859-0861 might transport an oligosaccharide containing a mannose moiety connected via its -1-position to the 6-position of the second glycose moiety or an aglycone. This assumption is based on the observation that the presumed operon contains also genes encoding an -1,6-glycosidase- and a phospho-mannomutase-like protein. The substrate is probably not methyl--D-mannopyranoside, because this compound is likely to be transported by a PTS. Fermentation of methyl--D-mannopyranoside was abolished in a ptsI deletion mutant (E. Milohanic and J. Deutscher, unpublished results). No reliable predictions can be made for the substrate of the ABC transporter encoded by Lmo0809-0811. This system possesses its own ATP hydrolyzing protein and the operon also encodes enzymes resembling carbonic anhydrase, fructokinase and oxidoreductase. The presumed fructokinase might not phosphorylate fructose, but possibly one of the other three ketohexoses (sorbose, tagatose, psicose) or a ketopentose.
C
ARBONS
OURCEM
EDIATEDR
EPRESSION OFV
IRULENCEG
ENES Like in most other firmicutes, the efficient utilization of a carbon source by L.monocytogenes leads to carbon catabolite repression, i.e., the genes encoding the proteins required for the uptake and metabolism of less efficient carbon sources are not expressed when glucose, fructose, mannose or other rapidly metabolized carbohydrates are present.
Several different mechanisms are used by bacteria to exert carbon catabolite repression [21].
The main mechanism in firmicutes is mediated by a complex formed between the catabolite control protein A (CcpA) and seryl-phosphorylated HPr (P-Ser-HPr) [88]. The signal for the formation of P-Ser-HPr is provided by metabolites, which accumulate (FBP, ATP) or vanish (Pi) during the utilization of an efficient carbon source [89]. Metabolites such as FBP and ATP stimulate and inorganic phosphate (Pi) inhibits the activity of the bifunctional HPr kinase/phosphorylase (HprK/P) [90]. This enzyme catalyzes the phosphorylation of HPr and dephosphorylation of P-Ser-HPr in response to changes of the intracellular concentration of the above-mentioned metabolites [89]. Dephosphorylation of P-Ser-HPr follows a unique phosphorolysis mechanism [91]. When glucose or other efficiently metabolized carbohydrates are present, the elevated amounts of FBP and ATP and the low Pi concentration will activate the kinase function and inhibit the phosphorylase activity of HprK/P and HPr will become phosphorylated in an ATP-requiring reaction at Ser-46 [92]. P-Ser-HPr interacts with CcpA [93] and the complex binds to specific operator sites on the DNA called catabolite response
elements (cre) [94, 95], which are usually located in the non-coding part of catabolic genes and operons and frequently overlap the promoter. Binding of the CcpA/P-Ser-HPr complex to the cre sites [96] prevents the expression of numerous catabolic genes. L. monocytogenes contains all the necessary components for CcpA-mediated carbon catabolite repression (HPr, CcpA, HprK/P and cre sites), and this mechanism has indeed been shown to be operative in the pathogen [10, 97].
P-Ser-HPr is also involved in two other, CcpA-independent mechanisms leading to the repression of catabolic genes. In the first CcpA-independent carbon catabolite repression mechanism the expression of numerous operons encoding PTS proteins is controlled by PTS regulation domain (PRD)-containing transcription activators or antiterminators. These regulators usually need to be phosphorylated by PEP, EI and HPr in order to be active.
Phosphorylation of HPr at Ser-46 drastically slows the PTS-mediated phosphoryl group transfer [98]. Formation of P-Ser-HPr therefore also slows phosphorylation of PRD-containing transcription activators and antiterminators which consequently are barely active.
In mutants deleted for ccpA several catabolic operons were still repressed by rapidly metabolizable carbon sources. In B. subtilis the CcpA-independent carbon catabolite repression disappeared when in addition either the phosphorylatable Ser-46 in HPr was replaced with Ala or the hprK gene was deleted [99], or when a mutant form of an antiterminator was used that did not require activation via phosphorylation by PEP, EI and HPr [100]. The LicT protein controls the expression of the bglPH operon of B. subtilis.
Deletion of CcpA prevented glucose repression of bglPH transcription initiation, but in the presence of glucose mRNA synthesis still stopped at the terminator preceding bglPH, thus leading to the synthesis of only a small RNA fragment. Only when in the ccpA mutant Ser-46 of HPr was replaced with Ala, the long bglPH transcript was synthesized even when glucose was present [99]. L. monocytogenes possesses an antiterminator-controlled operon (lmo2772-2771) resembling that of bglPH, which is preceded by a gene (lmo2773) encoding a LicT-like antiterminator. It is therefore likely that the regulation of lmo2772-lmo2771 expression resembles that of B. subtilis bglPH. In addition, there is a second L. monocytogenes antiterminator (Lmo2436), which also strongly resembles LicT, for which, however, the target gene or operon is not known. Finally, genetic studies with manR mutants suggested that the transcription activator of the L. monocytogenes glucose/mannose operon, ManR, needs to be phosphorylated by EI and HPr in order to be active [101]. In addition, expression of the man operon was strongly diminished in a ptsI deletion mutant unable to form P~His-HPr [14].
The second CcpA-independent carbon catabolite repression mechanism affects gene expression only indirectly by inhibiting carbohydrate uptake. Because the transported carbohydrate itself or one of its catabolites acts as inducer of the corresponding operon, this regulatory phenomenon was called inducer exclusion. In enterobacteria inducer exclusion seems to be the major mechanism of carbon catabolite repression [21]. Unphosphorylated EIIAGlc interacts with numerous transport proteins and inhibits their activity. In firmicutes, inducer exclusion seems to be mediated by P-Ser-HPr. The presence of glucose entirely inhibits maltose uptake in L. casei [87] and maltose and ribose uptake in Lactococcus lactis [102]. However, mutants unable to form P-Ser-HPr take up maltose even in the presence of glucose. In contrast, a L. casei mutant converting most of its HPr into P-Ser-HPr was not able to utilize maltose, even when glucose was absent [83]. Maltose utilization by L.
monocytogenes also seems to be regulated via inducer exclusion [84]. Deletion of ccpA did
not prevent the repressive effect of glucose on the expression of the malEFG operon.
However, when hprK was disrupted, glucose no longer repressed malEFG expression and no longer inhibited maltose uptake. Because the hprK mutant is not able to form P-Ser-HPr both, CcpA-mediated carbon catabolite repression and inducer exclusion, are no longer functional.
Finally, glucose kinase was also reported to be involved in carbon catabolite repression of certain organisms [103, 104]. However, the underlying mechanism is still poorly understood.
Several virulence genes of L. monocytogenes are also repressed by the presence of rapidly metabolizable PTS carbon sources, such as cellobiose, glucose, mannose or fructose, with cellobiose exhibiting the strongest repressing effect [8, 9]. The non-PTS sugars glucose-6-P and glycerol [11] do not repress the expression of virulence genes. Carbon source-mediated virulence gene expression was found to affect the activity of the Crp-like virulence gene activator PrfA and not the expression level of the prfA gene, thus suggesting a direct interaction of the repressor/activator compound with PrfA. PrfA binds to conserved 14 bp sequences of dyad symmetry preceding the promoter sequences in its target genes and operons [6, 105, 106]. Certain mutations were found to enhance the transcription activity of PrfA [107, 108], whereas other naturally occurring mutations inhibited it [109]. Interestingly, one of the stimulating mutations (Gly145Ser) was in the same region of the protein as one of the activating mutations (Gly141Ser) identified for Crp [107]. Because several distinct mutations led to the activation of PrfA, it was assumed that the PrfA effector compound would stimulate PrfA activity. The stimulating mutations are thought to mimic the structural changes which occur when the effector molecule binds to PrfA. However, it cannot be excluded that the stimulating mutations might prevent the binding of an inhibiting effector compound. A PrfA activating factor (Paf) present in L. monocytogenes crude extracts was found to enhance binding of PrfA to its DNA targets [110]. However, Paf was later identified as RNA polymerase. Because PrfA is essential for virulence gene expression [6], a relief from repression of the L. monocytogenes virulence genes can only be observed in strains in which the transcription activator PrfA is functional [14]. Inhibition of virulence gene expression by carbon sources is not mediated via the main carbon catabolite repression mechanism because it is CcpA independent [10] and P-Ser-HPr also does not seem to play a direct role [50, 111].
Certain results suggested that two semi-independent mechanisms of carbon source-mediated virulence gene repression might exist in L. monocytogenes [112]. One mechanism was thought to specifically control cellobiose-mediated virulence gene repression, whereas the second mechanism was assumed to be operative for all other repressing carbohydrates. The cellobiose-specific inhibition of the hemolysin-encoding hly gene was strongly reduced when the csrA gene (csr = cellobiose-specific regulation) became inactivated. In fact, it was later found that the PRD-containing transcription activator CsrA controls the expression of the genes encoding the major cellobiose transporter (2685) and similar to the lmo2683-2685 deletion strain [19] the csrA mutant probably utilizes cellobiose less efficiently, which might explain the observed partial relief from virulence gene repression. A second mutation (gcr, for general catabolite regulation) prevented repression of virulence gene expression by several carbon sources, including glucose. Nevertheless, in a csrA, gcr double mutant -glucosidase activity was still repressed by glucose and other efficiently utilized carbon sources, confirming that carbon catabolite repression and virulence gene repression are mediated by two distinct mechanisms. The double mutant also exhibited complete relief from cellobiose repression. Unfortunately, the gene altered by the gcr mutation could not be identified.
A transposon insertion affecting the PRD-containing antiterminator BvrA, which controls the expression of the bvrABC operon, and BvrB, an EIIBCA PTS component of the glucose/glucoside family, prevented repression of the virulence gene plcB by cellobiose and the -glucoside salicin [49]. The closely related -heteroside arbutin still repressed virulence gene expression because it is probably transported by a different PTS. The reason why the transposon insertion causes a relief from virulence gene expression is not understood. The findings that mutations in transcription regulators of PTS genes affected PrfA activity suggested that PTS components might be directly or indirectly involved in virulence gene repression.
Because PTS components are barely phosphorylated at their conserved cysteine or histidine residue when glucose or other efficiently metabolizable carbon sources are utilized [113, 114], it was assumed that either an unphosphorylated PTS component might inhibit the activity of PrfA or a phosphorylated PTS protein might stimulate the transcription activator.
The latter possibility became unlikely when it was found that deletion of the L.
monocytogenes EI-encoding ptsI gene led to strong expression of virulence genes when the cells were grown in glucose-containing medium [14] or in the presence of cellobiose or fructose (F. Aké, E. Milohanic and J. Deutscher, unpublished results). In a L. monocytogenes ptsI mutant, all PTS proteins are present in dephosphorylated form, similar as in cells growing on an efficiently utilized PTS substrate. Deletion of ptsI was therefore rather expected to cause permanent inhibition of virulence gene expression and not a relief from repression. One possible explanation for the high level expression of the virulence genes in the ptsI mutant is that unphosphorylated EI might inhibit PrfA activity in a direct or indirect way, which, of course, is prevented when EI is deleted. A more likely explanation for the phenotype of the ptsI mutant is that this strain is not able to efficiently transport PTS sugars and as a consequence virulence genes are not repressed. This concept is supported by the finding that a ptsH mutant, which is also unable to transport PTS sugars, exhibited elevated expression of the virulence genes similar to the ptsI mutant [50]. Nevertheless, HPr or one of its phosphorylated derivatives might play a role in virulence gene repression. When an hprK deletion mutant, which is unable to form P-Ser-HPr, was grown in glucose-containing medium expression of the L. monocytogenes virulence genes was strongly upregulated.
Complementation of the mutant with an hprK wild-type allele restored glucose-mediated repression of the virulence genes. This suggests that P-Ser-HPr, the amount of which drastically increases during the uptake and metabolism of efficient carbon sources [114], might function as direct or indirect inhibitor of PrfA activity. Based on expression studies of a PrfA-controlled reporter gene in a PrfA-producing B. subtilis strain and in hprK, ptsI and ptsH mutants derived from it, P-Ser-HPr had already previously been proposed to play a role in PrfA regulation [111]. However, when L. monocytogenes wild-type cells were grown in the presence of various carbon sources, the amount of P-Ser-HPr formed during utilization of the different carbohydrates did not correlate with the repressive effect on PrfA activity [50].
Specifically, during growth on cellobiose, which has the strongest repressive effect on virulence gene expression, only a small amount of P-Ser-HPr was formed. It was therefore concluded by the authors that P-Ser-HPr does not play a role in the repression of virulence gene expression.
Because none of the general PTS components seemed to be involved in carbon source-mediated repression of L. monocytogenes virulence genes, sugar-specific EII‘s were considered to play a role in the regulation of PrfA activity. A potential interaction of
components of the PTSMan with PrfA was suggested by the observation that overexpression of PrfA inhibited glucose uptake and consequently also growth of L. monocytogenes in glucose-containing medium [115]. In a later study, the EIIABMan component of the major mannose and glucose transporter was proposed to carry out this function, because relief from glucose repression was stronger in a manL deletion strain (encodes EIIABMan) than in a mutant lacking manM (encodes EIICMan), although both strains should show an identical loss of their capacity to transport glucose via the PTSMan [14]. However, the manL deletion caused a relief from virulence gene repression only for cells grown on glucose or mannose, but not for cells grown on cellobiose or fructose (F. Aké, E. Milohanic and J. Deutscher, unpublished results), thus excluding the possibility that EIIABMan might function as a general repressor of PrfA activity.
The possibility was therefore also considered that a metabolite, most likely a glycolytic intermediate, might control the activity of PrfA. The intracellular concentration of certain glycolytic intermediates, such as glucose-6-P and fructose-1,6-bisphosphate, changes drastically when an efficiently metabolizable carbon source is utilized by bacteria [116].
However, no metabolite has so far been identified that would affect the binding of PrfA to its DNA targets in electrophoretic mobility shift assays (F. Aké, E. Milohanic and J. Deutscher, unpublished results); [11]. Second messengers were also suspected to regulate PrfA activity, especially as Crp is regulated by cAMP. The effect of cAMP, cGMP, cyclic-di-AMP and others on the binding of PrfA to its DNA targets was also tested (F. Aké, E. Milohanic and J.
Deutscher, unpublished results). Again, none of these compounds had an effect on the interaction of PrfA with its DNA targets during electrophoretic mobility shift assays with PrfA and appropriate DNA fragments.
In conclusion, although first reported about 20 years ago, the mechanism leading to carbon source-mediated repression of most of the L. monocytogenes virulence genes is still not understood.
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Chapter 4