Trends in Microbiology
Cyclomodulins: bacterial effectors that modulate the eukaryotic cell cycle
Introduction
Many pathogens, when infecting a host, manipulate its signal-transduction pathways to survive. With progress in our understanding of the molecular mechanisms that bacteria use to attach to, enter into, move within and multiply inside host cells, it came to light that microbial pathogens have developed sophisticated mechanisms to block or subvert normal host-cellular processes, thereby contributing to colonization and pathogenesis. Many pathogenic bacteria adhere to and subsequently invade host cells by injecting their own proteins (which often mimic eukaryotic cell ligands) into host cells to target the cytoskeleton and various signal-transduction pathways. Manipulation of host-cell components, such as Rho GTPases, induces membrane ruffling and enables bacterial invasion. Pathogens that remain within a vacuole after bacterial invasion can control host-cell vesicular transport and endocytosis. Other pathogens can prevent their own uptake by phagocytic cells and/or kill them by triggering host-programmed cell death. Thus, there are several examples showing how bacterial pathogens hijack essential host functions, such as cytoskeleton assembly and apoptosis control (reviewed in Ref. [1]). However, until recently, little attention has been paid to emerging evidence that bacteria also have virulence mechanisms that target the cell cycle. Similar to the many viruses that perturb cell-cycle cellular machinery to suit their replication scheme [2], a growing number of pathogenic bacteria are also able to interfere actively with the host cell cycle. We propose the use of the term ‘cyclomodulins’ to describe this growing family of bacterial molecules that modulate the eukaryotic cell cycle. In this review, we describe the prominent members of the cyclomodulins, discuss their putative role in the natural history of disease and their potential implication in the cause of cancer.
Section snippets
Cytolethal distending toxin: a paradigm for cyclomodulins?
Cytolethal distending toxin (CDT) is the first bacterial toxin to be shown to block the host cell cycle at the transition between the G2 [preparation stage between the S (synthesis) phase and the M (mitosis) phase] and M phases [3] (Figure 1). Several pathogenic bacteria produce CDT, including Escherichia coli, Shigella dysenteriae, Campylobacter spp., Salmonella typhi, Haemophilus ducreyi, enterohepatic Helicobacter species (i.e. Helicobacter hepaticus) and Actinobacillus actinomycetemcomitans
Cyclomodulins promoting cellular proliferation
Infections caused by several bacteria (e.g. Helicobacter pylori, Bartonella spp., Lawsonia intracellularis and Citrobacter rodentium) can induce cellular proliferation, and in the case of H. pylori this has been associated with the development of cancer [33]. Several bacterial products are known to stimulate the proliferation of eukaryotic cells (Table 1). These include Pasteurella multocida toxin (PMT), the cytotoxic necrotizing factors (CNFs) from E. coli (Figure 3) and the dermonecrotic
Putative role of cyclomodulins in bacterial virulence
What could the advantage be for a bacterial pathogen to interfere with the host cell cycle? A bona fide cyclomodulin inhibiting cellular proliferation probably exerts its effect on cells that normally undergo continuous replication, such as the intestinal epithelium, which goes through perpetual regeneration, fuelled by a population of multipotent stem cells located at the base of the crypts of Lieberkuhn or those associated with the immune system. By inducing cell-cycle arrest, these
Potential role of cyclomodulins in cancer
Several cyclomodulins have been shown to play a role in the virulence of different pathogenic bacteria but the main target might not be the host cell cycle as tested in the ‘classical’ infection models used to study the virulence of bacterial pathogens. Conversely, chronic infection with bacteria that perturb cell-signalling processes is highly likely to contribute to cell transformation by facilitating an anti-apoptotic proliferative state or genotoxic activity that encourages tumour
Concluding remarks
The emerging concept reviewed here is still in its infancy and many questions will have to be answered to begin to understand how bacteria can manipulate host key processes that control eukaryotic cell growth. Is the production of cyclomodulins common among bacteria? What evolutionary advantage can bacteria gain from the production of cyclomodulins? What is their role in disease, in cancer causation and progression? Do commensal bacteria produce cyclomodulins, and could these interfere with
Acknowledgements
Work done in our laboratory was supported by grants from the European Union Fifth Framework Quality of Life Program (QLK2–2000–00600 and QLK2-CT-2002–00944). We apologize to authors whose studies were not included as a result of space limitation.
References (62)
- et al.
Cytolethal distending toxin (CDT): a bacterial weapon to control host cell proliferation?
FEMS Microbiol. Lett.
(2001) Functionally unrelated signalling proteins contain a fold similar to Mg2+-dependent endonucleases
Trends Biochem. Sci.
(2000)An N-terminal segment of the active component of the bacterial genotoxin cytolethal distending toxin B (CDTB) directs CDTB into the nucleus
J. Biol. Chem.
(2003)The Haemophilus ducreyi cytolethal distending toxin induces cell cycle arrest and apoptosis via the DNA damage checkpoint pathways
J. Biol. Chem.
(2001)Study of the cytolethal distending toxin (CDT)-activated cell cycle checkpoint. Involvement of the CHK2 kinase
FEBS Lett.
(2001)Study of the cytolethal distending toxin-induced cell cycle arrest in HeLa cells: involvement of the CDC25 phosphatase
Exp. Cell Res.
(2000)Cellular microbiology: cycling into the millennium
Trends Cell Biol.
(1998)- et al.
How bacteria could cause cancer: one step at a time
Trends Microbiol.
(2002) Escherichia coli cytotoxic necrotizing factors and Bordetella dermonecrotic toxin: the dermonecrosis-inducing toxins activating Rho small GTPases
Toxicon
(2001)Cytotoxic necrotizing factor 1 from Escherichia coli and dermonecrotic toxin from Bordetella bronchiseptica induce p21(rho)-dependent tyrosine phosphorylation of focal adhesion kinase and paxillin in Swiss 3T3 cells
J. Biol. Chem.
(1997)
Toxin-induced activation of Rho GTP-binding protein increases Bcl-2 expression and influences mitochondrial homeostasis
Exp. Cell Res.
CNF1 exploits the ubiquitin-proteasome machinery to restrict Rho GTPase activation for bacterial host cell invasion
Cell
Pasteurella multocida toxin activates the inositol triphosphate signaling pathway in Xenopus oocytes via G(q)alpha-coupled phospholipase C-beta1
J. Biol. Chem.
Pleiotropic effects of Pasteurella multocida toxin are mediated by Gq-dependent and -independent mechanisms. involvement of Gq but not G11
J. Biol. Chem.
Pasteurella multocida toxin, a potent intracellularly acting mitogen, induces p125FAK and paxillin tyrosine phosphorylation, actin stress fiber formation, and focal contact assembly in Swiss 3T3 cells
J. Biol. Chem.
Helicobacter pylori and gastric diseases: a dangerous association
Cancer Lett.
The Pasteurella multocida toxin interacts with signalling pathways to perturb cell growth and differentiation
Int. J. Med. Microbiol.
Pathogenic trickery: deception of host cell processes
Nat. Rev. Mol. Cell Biol.
The cell cycle, cyclin-dependent kinases, and viral infections: new horizons and unexpected connections
Prog. Cell Cycle Res.
A new cytolethal distending toxin (CDT) from Escherichia coli producing CNF2 blocks HeLa cell division in G2/M phase
Mol. Microbiol.
CdtA, CdtB, and CdtC form a tripartite complex that is required for cytolethal distending toxin activity
Infect. Immun.
Interactions of Campylobacter jejuni Cytolethal Distending Toxin Subunits CdtA and CdtC with HeLa Cells
Infect. Immun.
Salmonella typhi encodes a functional cytolethal distending toxin that is delivered into host cells by a bacterial-internalization pathway
Proc. Natl. Acad. Sci. U. S. A.
Assembly and function of a bacterial genotoxin
Nature
A bacterial toxin that controls cell cycle progression as a deoxyribonuclease I-like protein
Science
DNase I homologous residues in CdtB are critical for cytolethal distending toxin-mediated cell cycle arrest
Mol. Microbiol.
Cellular internalization of cytolethal distending toxin from Haemophilus ducreyi
Infect. Immun.
The Haemophilus ducreyi cytolethal distending toxin activates sensors of DNA damage and repair complexes in proliferating and non-proliferating cells
Cell. Microbiol.
Campylobacter jejuni cytolethal distending toxin promotes DNA repair responses in normal human cells
Infect. Immun.
The Haemophilus ducreyi cytolethal distending toxin induces DNA double-strand breaks and promotes ATM-dependent activation of RhoA
Cell. Microbiol.
Escherichia coli CdtB mediates cytolethal distending toxin cell cycle arrest
Infect. Immun.
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