This Article
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Klose, K. E.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Klose, K. E.

Next Article 

Journal of Bacteriology, March 2006, p. 2025-2026, Vol. 188, No. 6
0021-9193/06/$08.00+0     doi:10.1128/JB.188.6.2025-2026.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

GUEST COMMENTARY

Increased Chatter: Cyclic Dipeptides as Molecules of Chemical Communication in Vibrio spp.

Karl E. Klose*

South Texas Center for Emerging Infectious Diseases and Department of Biology, University of Texas at San Antonio, San Antonio, Texas

Cell-to-cell communication in bacteria via chemical signal molecules has been intensively studied in the past decade, leading to an appreciation of the wide variety of mechanisms and overlapping systems bacteria use to communicate with each other and coordinate population-dependent gene expression. This phenomenon is commonly referred to as quorum sensing (QS) and has probably been best characterized in the Vibrio spp. Several different QS pathways have been elegantly characterized in Vibrio fischeri, V. harveyi, and V. cholerae; these pathways modulate bioluminescence, biofilm formation, and pathogenesis (for a review see reference 18). In the current issue, Park et al. (14a) describe a signaling molecule, cyclo-L-Phe-L-Pro (cFP) that fulfills some of the definitions of a QS molecule and may represent yet another means by which Vibrio spp. communicate.

QS was first described in V. fischeri and was shown to involve signaling through production of an acyl-homoserine lactone (AHL) molecule (14). The AHL-dependent QS systems are present in many bacterial species, and this type of signaling is believed to promote intraspecies communication, as, in general, each species makes a unique AHL that is recognized only by its cognate regulatory protein(s). The discovery of a second QS molecule in V. harveyi, frequently referred to as AI-2, revealed that, in this organism, parallel circuits exist and integrate two signaling pathways (AHL and AI-2 dependent) into a common response (1). AI-2 represents a family of dihydroxy-pentanedione molecules that are dependent on LuxS for synthesis, and LuxS is found in many different bacterial species (18). Thus, AI-2-dependent QS represents a mechanism for interspecies communication, and V. harveyi QS integrates information from both intra- and interspecies chemical signals.

Recently, third and fourth types of QS circuit have been described in V. cholerae. V. cholerae lacks an obvious AHL-dependent signaling system but has an AI-2-dependent circuit similar to that described in V. harveyi. In addition, V. cholerae has a QS signal cascade that recognizes an as yet unidentified molecule, referred to as CAI-1, that is dependent on CqsA for synthesis (11). Many, but not all, Vibrio spp. express CAI-1 (4). Moreover, V. cholerae has yet another sensory circuit that feeds information into the QS pathway through the CsrA protein (8). All three signaling cascades (AI-2, CAI-1, and CsrA dependent) converge to modulate the phosphorylation state of LuxO, and thus V. cholerae integrates three separate QS signals into a common signal transduction pathway, which likely allows for more-stringent control over QS-dependent behaviors (Fig. 1).


Figure 1
View larger version (15K):
[in this window]
[in a new window]
  		FIG. 1. Model of quorum sensing in Vibrio cholerae. See text for details. Quorum-sensing pathways responsive to AI-2 and CAI-1, as well as to a third molecule that has not yet been identified, converge to modulate the level of LuxO-phosphate (LuxO-P). LuxO-P represses the expression of HapR, and HapR represses the expression of TcpP. TcpP and ToxR coordinately activate the transcription of ToxT, which in turn activates expression of the virulence factors CT and TCP. ToxR, independently of TcpP, also activates CT expression, as well as OmpU. The cyclic dipeptide cFP, which has some characteristics of a QS molecule, appears to stimulate ToxR-dependent transcription of OmpU and CT.

In a screen for QS molecules from V. vulnificus that could stimulate AHL-dependent QS reporter strains, Park et al. (14a) identified a cyclic dipeptide molecule, cFP, rather than an AHL. cFP is released into V. vulnificus cell-free culture fluids in a density-dependent manner, with maximum concentrations present as cells enter stationary phase. Addition of both purified and chemically synthesized cFP altered gene expression in several Vibrio spp., including V. vulnificus, V. cholerae, V. parahaemolyticus, and V. harveyi. The most obvious effect of cFP in the various Vibrio spp. is the stimulation of the expression of the major outer membrane porin OmpU. OmpU transcription is modulated by the transmembrane regulatory protein ToxR (12), which is also essential for the virulence cascade responsible for expression of the major virulence factors cholera toxin (CT) and toxin coregulated pilus (TCP) in V. cholerae. The authors show that cFP also stimulates CT expression in V. cholerae, presumably through an effect on ToxR-dependent transcription. Since OmpU is known to enhance resistance to anionic detergents, organic acids, and antimicrobial peptides (9, 10, 15) and since CT is the cause of the characteristic fluid loss that is the hallmark of cholera, the authors conclude that cFP represents a potential QS molecule that contributes to the pathogenesis of Vibrio spp. Whether cFP represents a "true" QS molecule awaits further experimentation to uncover the molecular mechanism behind its mode of action.

The three QS pathways previously described in V. cholerae that converge to modulate LuxO-phosphate production have been shown to modulate the expression of virulence factors, including CT, by altering the expression of the global regulator HapR (20). The effect of cFP appears to be distinct from these other QS pathways, because cFP stimulates ToxR-dependent transcription, while the LuxO-dependent signals affect virulence through the modulation of levels of TcpP, another virulence-regulatory factor (Fig. 1). The LuxO-dependent pathway represses CT expression at high cell density, while cFP appears to stimulate CT expression at high cell density. These two phenomena are not as distinct as they might appear, however, given the complexity of the virulence cascade. While ToxR alone activates OmpU expression and can also activate CT expression (6), ToxR and TcpP cooperatively activate the expression of ToxT, which then activates CT and TCP expression (7). Therefore a scenario could be envisioned whereby cFP exerts its effects on the established QS pathways, which leads to altered TcpP-ToxR interactions, resulting in an indirect stimulation of genes that can be activated exclusively by ToxR.

While this alternate explanation may seem somewhat far-fetched, cFP, along with additional cyclic dipeptides, were previously characterized for their stimulation of AHL-dependent QS in Pseudomonas aeruginosa and Pseudomonas putida by "cross talk" (3, 5). Holden et al. (5) suggested that the Pseudomonas cyclic dipeptides compete for the AHL binding sites on the AHL-responsive regulator LuxR. Although no AHL-dependent QS has been described in V. cholerae, HapR could perhaps be bound by cFP, or cFP may bind one of the established QS receptors. A more attractive possibility that fits better with the observed cFP-dependent stimulation of OmpU expression in several Vibrio spp. is that cFP specifically alters ToxR-dependent transcription, perhaps by interacting directly with ToxR. ToxR transcriptional activity is known to be modulated by membrane-disruptive agents such as bile (16) and high pressure (19), which is not necessarily surprising for an integral membrane transcriptional activator, but no molecules have yet been described that directly bind to ToxR.

cFP belongs to a family of cyclic dipeptides referred to as diketopiperazines (DKP), and these molecules (including cFP) have been identified as having antifungal activity (17), antitumor activity (2), and antibacterial activity (13). The involvement of DKP in QS adds to the plethora of potential functions of these intriguing molecules. Does the involvement of cFP in QS represent an artificial cross-reactivity with established pathways that normally respond to related compounds? Or, is cFP a broad-spectrum molecule used to modulate the activity of both eukaryotic and prokaryotic cells in a density-dependent manner, and thus represents a novel molecule enabling interkingdom communication?

ACKNOWLEDGMENTS

I thank Bonnie Bassler for constructive comments on the manuscript.

I am funded by NIH AI43486 and AI51333.


arrow
FOOTNOTES
 
* Mailing address: Dept. of Biology, University of Texas San Antonio, 6900 N. Loop 1604 W., San Antonio, TX 78249. Phone: (210) 458-6140. Fax: (210) 458-4468. E-mail: kklose{at}utsa.edu. Back

FOOTNOTES

The views expressed in this Commentary do not necessarily reflect the views of the journal or of ASM.

REFERENCES

    1
  1. Bassler, B. L., M. Wright, and M. R. Silverman. 1994. Multiple signalling systems controlling expression of luminescence in Vibrio harveyi: sequence and function of genes encoding a second sensory pathway. Mol. Microbiol. 13:273-286.[Medline]
    2. 2
  2. Brauns, S. C., P. J. Milne, R. Naude, and M. Van de Venter. 2004. Selected cyclic dipeptides inhibit cancer cell growth and induce apoptosis in HT-29 colon cancer cells. Anticancer Res. 24:1713-1719.[Medline]
    3. 3
  3. Degrassi, G., C. Aguilar, M. Bosco, S. Zahariev, S. Pongor, and V. Venturi. 2002. Plant growth-promoting Pseudomonas putida WCS358 produces and secretes four cyclic dipeptides: cross-talk with quorum sensing bacterial sensors. Curr. Microbiol. 45:250-254.[CrossRef][Medline]
    4. 4
  4. Henke, J. M., and B. L. Bassler. 2004. Three parallel quorum-sensing systems regulate gene expression in Vibrio harveyi. J. Bacteriol. 186:6902-6914.[Abstract/Free Full Text]
    5. 5
  5. Holden, M. T. G., S. R. Chhabra, R. de Nys, P. Stead, N. J. Bainton, P. J. Hill, M. Manefield, N. Kumar, M. Labatte, D. England, S. Rice, M. Givskov, G. P. C. Salmond, G. S. A. B. Stewart, B. W. Bycroft, S. Kjelleberg, and P. Williams. 1999. Quorum-sensing cross talk: isolation and chemical characterization of cyclic dipeptides from Pseudomonas aeruginosa and other gram-negative bacteria. Mol. Microbiol. 33:1254-1266.[CrossRef][Medline]
    6. 6
  6. Hung, D. T., and J. J. Mekalanos. 2005. Bile acids induce cholera toxin expression in Vibrio cholerae in a ToxT-independent manner. Proc. Natl. Acad. Sci. USA 102:3028-3033.[Abstract/Free Full Text]
    7. 7
  7. Krukonis, E. S., R. R. Yu, and V. J. DiRita. 2000. The Vibrio cholerae ToxR/TcpP/ToxT virulence cascade: distinct roles for two membrane-localized transcriptional activators on a single promoter. Mol. Microbiol. 38:67-84.[CrossRef][Medline]
    8. 8
  8. Lenz, D. H., M. B. Miller, J. Zhu, R. V. Kulkarni, and B. L. Bassler. 2005. CsrA and three redundant small RNAs regulate quorum sensing in Vibrio cholerae. Mol. Microbiol. 58:1186-1202.[CrossRef][Medline]
    9. 9
  9. Mathur, J., and M. K. Waldor. 2004. The Vibrio cholerae ToxR-regulated porin OmpU confers resistance to antimicrobial peptides. Infect. Immun. 72:3577-3583.[Abstract/Free Full Text]
    10. 10
  10. Merrell, D. S., C. Bailey, J. B. Kaper, and A. Camilli. 2001. The ToxR-mediated organic acid tolerance response of Vibrio cholerae requires OmpU. J. Bacteriol. 183:2746-2754.[Abstract/Free Full Text]
    11. 11
  11. Miller, M. B., K. Skorupski, D. H. Lenz, R. K. Taylor, and B. L. Bassler. 2002. Parallel quorum sensing systems converge to regulate virulence in Vibrio cholerae. Cell 110:303-314.[CrossRef][Medline]
    12. 12
  12. Miller, V. L., and J. J. Mekalanos. 1988. A novel suicide vector and its use in construction of insertion mutations: osmoregulation of outer membrane proteins and virulence determinants in Vibrio cholerae requires toxR. J. Bacteriol. 170:2575-2583.[Abstract/Free Full Text]
    13. 13
  13. Milne, P. J., A. L. Hunt, K. Rostoll, J. J. Van der Walt, and C. J. Graz. 1998. The biological activity of selected cyclic dipeptides. J. Pharm. Pharmacol. 50:1331-1337.[Medline]
    14. 14
  14. Nealson, K. H., and J. W. Hastings. 1979. Bacterial bioluminescence: its control and ecological significance. Microbiol. Rev. 43:496-518.[Free Full Text]
    15. 14
  15. Park, D.-K., K.-E. Lee, C.-H. Baek, I. H. Kim, J.-H. Kwon, W. K. Lee, K.-H. Lee, B.-S. Kim, S.-H. Choi, and K.-S. Kim. Cyclo(Phe-Pro) modulates the expression of ompU in Vibrio spp. J. Bacteriol. 188:2214-2221.
    16. 15
  16. Provenzano, D., and K. E. Klose. 2000. Altered expression of the ToxR-regulated porins OmpU and OmpT diminishes Vibrio cholerae bile resistance, virulence factor expression, and intestinal colonization. Proc. Natl. Acad. Sci. USA 97:10220-10224.[Abstract/Free Full Text]
    17. 16
  17. Provenzano, D., D. A. Schuhmacher, J. L. Barker, and K. E. Klose. 2000. The virulence regulatory protein ToxR mediates enhanced bile resistance in Vibrio cholerae and other pathogenic Vibrio species. Infect. Immun. 68:1491-1497.[Abstract/Free Full Text]
    18. 17
  18. Strom, K., J. Sjogren, A. Broberg, and J. Schnurer. 2002. Lactobacillus plantarum MiLAB393 produces the antifungal cyclic dipeptides cyclo(L-Phe-L-Pro) and cyclo(L-Phe-trans-4-OH-L-Pro) and 3-phenyllactic acid. Appl. Environ. Microbiol. 68:4322-4327.[Abstract/Free Full Text]
    19. 18
  19. Waters, C. M., and B. L. Bassler. 2005. Quorum sensing: cell-to-cell communication in bacteria. Annu. Rev. Cell Dev. Biol. 21:319-346.[CrossRef][Medline]
    20. 19
  20. Welch, T. J., and D. H. Bartlett. 1998. Identification of a regulatory protein required for pressure-responsive gene expression in the deep-sea bacterium Photobacterium species strain SS9. Mol. Microbiol. 27:977-985.[CrossRef][Medline]
    21. 20
  21. Zhu, J., M. B. Miller, R. E. Vance, M. Dziejman, B. L. Bassler, and J. J. Mekalanos. 2002. Quorum-sensing regulators control virulence gene expression in Vibrio cholerae. Proc. Natl. Acad. Sci. USA 99:3129-3134.[Abstract/Free Full Text]

Journal of Bacteriology, March 2006, p. 2025-2026, Vol. 188, No. 6
0021-9193/06/$08.00+0     doi:10.1128/JB.188.6.2025-2026.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Recio, E., Aparicio, J. F., Rumbero, A., Martin, J. F. (2006). Glycerol, ethylene glycol and propanediol elicit pimaricin biosynthesis in the PI-factor-defective strain Streptomyces natalensis npi287 and increase polyene production in several wild-type actinomycetes.. Microbiology 152: 3147-3156 [Abstract] [Full Text]  

This Article
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Klose, K. E.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Klose, K. E.

Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»