Control of Listeria monocytogenes virulence by 5′-untranslated RNA

Update TRENDS in Microbiology Vol.14 No.7 July 2006294

6 Nichols, B.J. et al. (2001) Rapid cycling of lipid raft markers betweenthe cell surface and Golgi complex. J. Cell Biol. 153, 529–541

7 Sharma, P. et al. (2004) Nanoscale organization of multiple GPI-anchored proteins in living cell membranes. Cell 116, 577–589

8 Cover, T.L. and Blanke, S.R. (2005) Helicobacter pylori VacA, aparadigm for toxin multifunctionality. Nat. Rev. Microbiol. 3, 320–332

9 Schraw, W. et al. (2002) Association of Helicobacter pylori vacuolating

toxin (VacA) with lipid rafts. J. Biol. Chem. 277, 34642–3465010 Ricci, V. et al. (2000) High cell sensitivity to Helicobacter pylori VacA

Corresponding author: Johansson, J. ([email protected]).* Authors contributed equally.

Available online 26 May 2006

www.sciencedirect.com

toxin depends on a GPI-anchored protein and is not blocked byinhibition of the clathrin-mediated pathway of endocytosis. Mol. Biol.Cell 11, 3897–3909

11 Niedergang, F. and Chavrier, P. (2005) Regulation of phagocytosis byRho GTPases. Curr. Top. Microbiol. Immunol. 291, 43–60

12 Habermann, B. (2004) The BAR-domain family of proteins: a case ofbending and binding. EMBO Rep. 5, 250–256

0966-842X/$ - see front matter Q 2006 Elsevier Ltd. All rights reserved.

doi:10.1016/j.tim.2006.05.002

Genome Analysis

Control of Listeria monocytogenes virulenceby 5 0-untranslated RNA

Edmund Loh*, Jonas Gripenland* and Jorgen Johansson

Department of Molecular Biology, Umea University, S-901 87 Umea, Sweden

The Gram-positive bacterium Listeria monocytogenes

uses a wide range of virulence factors for its patho-

genesis. Expression of five of these factors has

previously been shown to be subjected to post-

transcriptional regulation as a result of their long

5 0-untranslated region (5 0-UTR). We have investigated

the presence of 5 0-UTRs among the other known

virulence genes and genes that encode putatively

virulence-associated surface proteins. Our results

strongly suggest that L. monocytogenes controls

many of its virulence genes by a mechanism that

involves the 5 0-UTR. These findings further emphasize

the importance of post-transcriptional control for

L. monocytogenes virulence.

Listeria monocytogenes virulence regulation

Listeria monocytogenes is a Gram-positive, facultativeintracellular bacterium that causes severe food-borneinfections in humans and animals [1]. By using differentadhesins, Listeria has the ability to bind and invademammalian cells. L. monocytogenes uses the pore-forminglisteriolysin O (LLO) and a phospholipase (PI-PLC) toescape the phagocytic vacuole that is formed afterinvasion. With the help of ActA, the bacterium canpolymerize actin, which enables movement into theneighboring cell. Thus far, 19 virulence factors havebeen identified in L. monocytogenes [1–6]. 15 of thesefactors are encoded by genes that belong to monocistronicunits or by the first gene of a polycistronic messenger and,therefore, are preceded by 5 0-untranslated RNAs ofvarious lengths.

Recently, it has been shown that the translation ofthree L. monocytogenes virulence determinants (inlA, hlyand actA) is controlled by their 5 0-untranslated region

(5 0-UTR) [7–9]. These observations, together with theidentification of a 5 0-UTR-located thermosensor thatprecedes the virulence regulator PrfA [10] and the post-transcriptional regulation of p60 expression [11], clearlydemonstrate that pathogenesis can be controlled byrelatively long untranslated RNA regions in front ofvirulence genes. In light of this, we were curious todetermine the presence of long 5 0-UTRs among the otherknown virulence factors and within intergenic regionspreceding genes that encode L. monocytogenes surfaceproteins. We reasoned that the presence of a large UTR infront of a virulence gene gave a strong indication of itbeing post-transcriptionally regulated.

Here, we show that many listerial virulence-associatedgenes are preceded by long 5 0-UTRs and suggest thatL. monocytogenes has a large collection of virulence genesthat are post-transcriptionally regulated.

Post-transcriptional regulation of virulence genes:

known cases

The best-understood example of post-transcriptionalregulation in L. monocytogenes is the prfA thermosensor,in which the UTR controls translation [10]. At lowtemperatures (!308C), the 5 0-UTR of prfA forms asecondary structure that masks the Shine-Dalgarno (SD)site and prevents translation. At higher temperatures(378C), this secondary structure is partially disrupted,which enables binding of the ribosome and translation.prfA transcription initiates from two promoters(prfA P1 and P2), at which the P1 transcript mediatesthermosensing.

In contrast to the repressive effect of the UTR for theexpression of prfA, an intact UTR is required for maximalexpression of InlA, ActA and LLO (gene products of inlA,actA and hly, respectively [7–9]; Table 1) and forL. monocytogenes virulence. In all cases, partial deletionsof the UTRs decrease the expression of the gene products,although no specific sequences have been identified that

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Table 1. Known virulence factors regulated by an UTR-dependent mechanism

Gene name IG locationa Directionb Size of intergenic

region (bp)

Size of UTR (nts)c Putative role or

functiond

Refs

actA 209272–209469 O T O 198 150 sA Unknown [9]

hly 205578–205818 ! OO 241 133 sA, 121 sA Unknown [8]

iap 620381–620804 ! OO 424 70 sA Unknown [11]

inlA 453854–454533 O T O 680 440 sB, 396 sA, 391 sA STAB-SD? [7,14,27]

prfA 204354–204623 O T O 270 115 sA, 31 sB Thermosensor [10]

Known virulence factors possibly regulated by an UTR-dependent mechanism

bilE 1451598–1451812 ! OO 215 77 sB, 26 sA Unknown [3]

bsh 2147427–2147683 O T O 257 104 sA, 33 sB Structural switch? [1,27], this work

inlC 1861091–1861906 O T O 816 99 sA STAB-SD? [2], this work

mpl 207409–207738 O OO 330 151 sA Unknown [17]

uhpT 868801–869094 O T O 294 144 sA STAB-SD? [18], this workaIntergenic location according to http://genolist.pasteur.fr/ListiList/.bArrow to the left indicates the direction of the upstream gene in relation to the UTR/putative UTR (bold). Presence of a transcriptional terminator structure in between the

upstream gene and the UTR or putative UTR is denoted by a T.cSize of UTRs in nucleotides (nts). Transcripts either start from a sA-dependent or a sB-dependent promoter.dSee main text for additional comments.

Update TRENDS in Microbiology Vol.14 No.7 July 2006 295

are particularly important for stimulation. We believe it isunlikely that the post-transcriptional regulation of inlA,actA and hly occurs by a thermosensing mechanism,primarily because these genes are PrfA-regulated and,hence, almost exclusively expressed at 378C. In the case ofLLO, the 5 0-UTR is more important during the infectionprocess and less important during growth in broth culture,which suggests that the bacterium can sense its presenceinside the host and adjust the expression of LLOaccordingly [8]. Such a mechanism is probably alsoevident for at least ActA because its expression isdramatically induced intracellularly [12].

There is no obvious mechanism by which the afore-mentioned UTR structures can stimulate the expression oftheir gene product, although one of the following twopathways is the most probable.

(i) Stability of messenger: in Gram-positive bacteria,5 0-UTRs can stabilize the messenger against ribonu-cleases. This is achieved by hairpin structures, RNAbinding proteins and by sequestered ribosomes [13]. Insome cases, ribosome sequestration is dependent onSTAB-SD (stability-SD), a sequence that mimics a nativeSD site and is located at the 5 0-end of the UTRs [14].Binding of the ribosome to STAB-SD decreases theaccessibility of the ribonuclease to the 5 0-UTR and therebystabilizes the transcript. Interestingly, it has beensuggested that the 5 0-end of the inlAB transcript harborssuch a STAB-SD site ([14]; see online SupplementaryMaterial, Figure S1). Moreover, there is a correlationbetween the amount of transcript and the final geneproduct for inlA and hly, which suggests that the post-transcriptional regulation is exerted at the level oftranscript stability [7,8].

(ii) Initiation of translation. Upon binding to specificmetabolites (riboswitches [15]) or by altering the tempera-ture (thermosensors [10]), the UTR can alter its confor-mation, which results in modulated binding of theribosome to the SD. In the case of riboswitches, base-pairing between an anti-SD site and an anti-anti-SD sitedetermines the accessibility of the SD in response tometabolite concentrations. Therefore, it can behypothesized that a putative host factor, or a bacterialfactor induced by the host, binds to the UTR and therebycontrols the initiation of translation of the virulence gene.


However, no obvious possible alterations in the UTRstructure of hly and actA that would change theaccessibility to the SD site were found when the UTRswere folded in silico by the mfold program (data notshown; http://www.bioinfo.rpi.edu/applications/mfold/).However, it should be noted that deletions within theactA UTR that mostly affected ActA levels also changedthe UTR-structure most severely [9]. In the case of p60,expression seems to be controlled at a post-transcriptionallevel, at which the UTR of iap (encoding p60) probablyforms a structure that masks the SD site [11]. Owing tothe size of the iap UTR (70 nucleotides), we consider thatthis length is the minimal size that supports post-transcriptional regulation in this study.

Small non-coding RNAs (ncRNAs) control geneexpression at both the level of mRNA stability and thelevel of translation initiation [16]. Therefore, suchncRNAs could control the expression of InlA, LLO andActA. We performed an extensive search for putativencRNAs complementary to the inlA, hly and actA UTRsbut were unable to find any RNA structures that displayedany considerable complementarity (data not shown),which strongly argues that the mechanism by which theUTRs function does not involve ncRNAs.

Post-transcriptional regulation: other known virulence

factors

The coding RNAs of several other known virulence factorsin L. monocytogenes are preceded by long UTRs (O70nucleotides). These are inlC, mpl, uhpT, bsh and bilE (sB

regulated) [1–3,17,18]. The other virulence factors (plcB,inlB, srtA, virR) are not the first genes of an operon andanother, plcA, has a short UTR. This suggests that theselatter virulence factors are not controlled post-transcrip-tionally, although inlB and plcB might indirectly becontrolled post-transcriptionally because they are presentjust downstream of inlA and actA, respectively. For theremaining virulence genes (vip, inlJ, fbpA, auto and ami[4,6,19–21]), the transcriptional start sites are not known.However, their genes are all preceded by large intergenicregions and they are the first genes of an operon. Weanalyzed the intergenic region that precedes these genesand searched for promoters to find putative UTRs in frontof the downstream gene. In addition to sA consensus sites,

http://www.bioinfo.rpi.edu/applications/mfold/

http://genolist.pasteur.fr/ListiList/



we chose to search for sB consensus sites because thissigma factor is involved in virulence [22]. To determine thesensitivity and selectivity of the computational method,the number of known promoters and false-positivepromoters were identified: 71% (10 out of 14) of knownsB and 58% (14 out of 24) of known sA L. monocytogenespromoters were found, and 7% of sB promoters and 38% ofsA promoters were identified as false-positives. A difficultyof studying sA promoters involved in L. monocytogenesvirulence is that they are frequently regulated by PrfAand, therefore, show a weak K35 site. Consequently, onlyfour out of ten (40%) of the PrfA-regulated promoters were

Table 2. Size of intergenic regions and putative UTRs preceding ge

Gene name IG locationb Directionc Size of intergenic

region (bp)

ami 2634851–2635166 ! OO 316

fbpA 1903996–1904151 ! OO 156

inlE 286012–286218 O T O 207

inlF 429404–429629 O T O 226

inlG 282482–282754 O T O 273

inlH 284228–284364 O T O 137

Lmo0130 133774–133960 ! OO 187

Lmo0159 156806–157088 O T O 283

Lmo0160 159471–159662 O T O 192

Lmo0171 169271–169509 O T O 239

Lmo0175 174557–174833 ! OO 277

Lmo0320 vip 346050–346376 ! OO 327

Lmo0327 351265–351458 O T O 194

Lmo0331 359677–360171 ! OO 495

Lmo0333 360508–360935 O T O 428

Lmo0394 416653–416795 O T O 143

Lmo0435 458914–459680 O T O 767

Lmo0514 547139–547519 ! OO 381

Lmo0610 651634–651793 O T O 160

Lmo0627 663937–664241 ! OO 305

Lmo0725 756292–756493 ! OO 202

Lmo0732 760860–761551 O T O 692

Lmo0801 828017–828167 O T O 151

Lmo0842 875259–875720 O T O 462

Lmo0880 918903–919019 O T O 117

Lmo1076 auto 1105865–1106040 O T O 176

Lmo1115 1152476–1153009 ! OO 534

Lmo1136 1169542–1170001 O T O 460

Lmo1215 1235331–1235669 O T O 339

Lmo1289 1313325–1313653 O T O 329

Lmo1290 1315436–1315766 O T O 331

Lmo1413 1443688–1443872 O T O 185

Lmo1521 1553910–1554359 ! OO 450

Lmo1799 1872244–1872723 O T O 480

Lmo2026 2108210–2108499 O T O 290

Lmo2085 2164012–2164105 O T O 94

Lmo2179 2268231–2268423 O T O 193

Lmo2203 2293175–2293496 ! OO 322

Lmo2396 2468704–2469092 ! OO 389

Lmo2576 2657804–2657023 O T O 220

Lmo2591 2679331–2679598 ! OO 268

Lmo2714 2788364–2788503 O T O 140

Lmo2821 inlJ 2906941–2907152 ! OO 212aAbbreviation: ND, not determined. Consensus sites for sA and sB were not found.bIntergenic location according to http://genolist.pasteur.fr/ListiList/.cArrow to the left indicates the direction of the upstream gene in relation to the UTR/pu

upstream gene and the UTR or putative UTR is denoted by a T.dSize of predicted UTRs in nucleotides (nts). Promoter candidates were identified using t

consensus: sA: TTGACA-n16–18-TATAAT. Candidates with a 17-nucleotide space were con

harboringG at position threewere considered essential because of the lowGC content in

promoters are within parentheses. sB consensus: GTTT-n15–16-GGGA/TAT, in which G in

surface proteins (lmo0880 and lmo2085) shown to be sB regulated by Kazmierczak et

sequence of intergenic regions and promoter candidates.eSee main text for additional comments. Putative novel ncRNAs are denoted by ‘ncRNA

UTR.


correctly identified. This is in contrast to non-PrfAregulated genes in which 10 out of 14 (71%) of thepromoters were recognized.

Our results (Table 2; see also online SupplementaryMaterial, Table S1) suggest that inlJ, vip and fbpA harborlong UTRs (125, 290 and 75 and 120 nucleotides,respectively). Considering the correlation between largeUTRs (O70 nucleotides) and post-transcriptional controlof prfA, hly, actA, inlA and iap expression, we believe thatthe presence of a large UTR increases the probability ofpost-transcriptional regulation of the downstream gene.Hence, we suggest that the expression of InlC, Mpl, UhpT,

nes that encode surface proteinsa

Predicted size of UTR (nts)d Putative role

or functione

Refs

sA sB

53 Unknown This work

120, 75 Unknown This work


(136) Unknown This work


(48) 58 Unknown This work









(366), 326, (84) Unknown This work



163, 26 104 Unknown This work

61 51 Unknown This work

NDa Unknown This work


364, 256, 191 ncRNA? ) This work

NDa Unknown This work

302, 252 STAB-SD? This work

29 Unknown [27], this work


381, (320) Unknown This work


116, 51, 35 ncRNA? ) This work


208 ncRNA? ) This work


75 ncRNA? ) This work

357 142 Unknown This work

96, 19 34 Unknown This work

31 Unknown [27], this work


126, 88 Unknown This work






tative UTR (bold). Presence of a transcriptional terminator structure in between the

he ‘Extended Search’ option at http://genolist.pasteur.fr/ListiList/ with the following

sidered more relevant than candidates with a 16- or 18-nucleotide space.K35 sites

Listeriamonocytogenes. Candidateswere analyzed and judged individually.Weaker

GTTT was considered essential [27] and one mismatch per box was allowed. Both

al. [27] were identified by our analysis. See Supplementary Material Table S1 for

?’ and the direction of the arrow relates its putative position to the UTR or putative




Update TRENDS in Microbiology Vol.14 No.7 July 2006 297

Bsh, BilE, FbpA, InlJ and Vip is controlled by a post-transcriptional mechanism (Table 1 and Table 2). Strik-ingly, the UTRs of both inlC and uhpT seem to harborSTAB-SD sites close to their transcriptional start site (seeonline Supplementary Material, Figure S1). As suggestedfor InlA, such sites could stabilize these transcripts [14].Moreover, the 5 0-UTR of bsh seems to have the ability toswitch between two structures, one in which the SD seemsto be sequestered in a hairpin and one in which the SD isfree (see online Supplementary Material, Figure S2),which implies that the expression of bsh is controlled atthe level of translation initiation.

Surface proteins

It has been suggested that many still-unknown virulencefactors reside within various surface proteins [23]. Suchfactors might enable the binding of L. monocytogenes todifferent cells. This gives the bacterium cell-specificitywithin various organs.

To examine if mRNAs encoding these surface proteinscould also harbor large UTRs, we examined the intergenicregions preceding their genes. First, in many cases (38 outof 47), these genes were the first gene in either mono- orpolycistronic operons. Second, on average, the size of theseintergenic regions was 269 basepairs, compared with theaverage size of the intergenic region of the first 300 genes inL. monocytogenes, which was 104 basepairs. These twocircumstances strongly suggested that a large piece ofinformation resides within these intergenic regions andthat they could possibly harbor long UTRs. To investigate ifthis was the case, we examined the intergenic regionpreceding genes that were first in an operon. Several (50%)of the mRNAs encoding surface proteins could be precededby long UTRs (Table 2) and might be controlled post-

Increasedtemperature

SD

prfA pr

PrfA

x

First level:

Second level:

PrfA-dependent pathway

prfAmRNA

Virulence genes+

Virulence proteins

mRNA 3′ 5′

Figure 1. Multiple levels of virulence control in Listeria monocytogenes. First level: Expres

prevents binding of the ribosome to the SD site. An increase in temperature enables the r

expression of several virulence genes (except iap). Some of these genes (and iap) are al

speculate that within the host, the 5 0-UTRs are subject to specific regulation, which lead


transcriptionally as suggested by the earlier arguments.Importantly for the accuracy of the promoter identification,none of the genes encoding surface proteins (Table 2) arePrfA-regulated except vip and inlH [24]. Therefore, thesepromoters probably harbor a more ‘classical’ sA promoterand should, accordingly, be more identical to the sA

promoter consensus. Some mRNAs seem to be expressedfrom multiple transcriptional start points and by both sA

and sB. Therefore, it could be hypothesized that variablepromoter usage enables the gene product to be expressed bya UTR-dependent and a UTR-independent mechanism inresponse to environmental (host) stimuli. Within theseintergenic regions, several putative terminators were alsoidentified that were mostly located in the opposite directionof the adjacent ORFs, thus suggesting the presence ofncRNAs (Table 2).

Concluding remarks and future perspectives

In this study, we have analyzed untranslated RNA regionsand intergenic regions located in front of genes that encodeknown virulence factors and surface proteins in Lmonocytogenes. Our results suggest that many such factorsharbor large UTRs. Because 5 0-located UTRs are respon-sible for post-transcriptional regulation of several viru-lence factors in L. monocytogenes [7–11], we suggest thatthe expression of many of the other genes involved inpathogenesis in L. monocytogenes are controlled post-transcriptionally, possibly involving a direct interactionbetween the UTR and a bacterial or host factor (Figure 1). Itis probable that the expression of several virulence genes inother pathogenic bacteria is also controlled post-transcrip-tionally, and such examples have been reported [25,26].

In the future, it will be essential to determine themechanism by which inlA, hly, actA, iap and other UTR-

SD

fA

PrfA

PrfA-independent pathway

Factors?(Bacterialor host) P60

Full virulence

iap

5′ 3′

TRENDS in Microbiology

sion of PrfA is controlled by a thermosensingmechanism in which low temperature

ibosome to bind to the site and translation can proceed. Second level: PrfA activates

so controlled by a post-transcriptional mechanism involving their 5 0-UTR (red). We

s to precise expression of the appropriate virulence factor at the right moment.



regulated genes are controlled. The correlation betweenthe size of the UTR and possible post-transcriptionalregulation should be examined. It is advisable to clearlydetermine the 5 0-end of the transcript by RACE (rapidamplification of cDNA ends) to be certain that the 5 0-endidentified by primer extension is not a result of transcriptdegradation. The stability of the transcript could becompared between bacteria growing in flasks (in vitro)and intracellularly (in vivo) by quantitative real-timePCR. If a difference is detected, it would indicate that thetranscript is controlled at the level of stability. If not, adifference in the ratio between transcript and proteinwithin bacteria grown in vitro and in vivo would suggestregulation at the level of translation. To elucidate theexact post-transcriptional mechanism, various point anddeletion mutants in the UTR can be constructed that affectthe expression of the gene product. Also, variousbiochemical analyses would verify the structure of theUTR, information that is essential to understand themechanism. Finally, if the structure of the UTR isswitched after binding a factor, this factor (bacterial orhost) should be determined genetically or biochemically.

Clearly, evolution has preserved this kind of regulationand it adds an additional layer of virulence control inL. monocytogenes (Figure 1). Such regulatory controlmight be of great importance during the course of infectionand our findings emphasize the broadness of its scope.

Acknowledgements

We thank C. Balsalobre, P. Cossart and P. Mandin for critical reading ofthe manuscript. J.J. is supported by the Wenner-Gren Foundations,Umea University and the Swedish Research Council grant 15144.

Supplementary data

Supplementary data associated with this article can befound at doi:10.1016/j.tim.2006.05.001

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Control of Listeria monocytogenes virulence by 5′-untranslated RNA