<i>Escherichia coli</i>CdtB Mediates Cytolethal Distending Toxin Cell Cycle Arrest

Elwell, Cherilyn A.; Chao, Kinlin; Patel, Kamlesh D.; Dreyfus, Lawrence A.

doi:10.1128/iai.69.5.3418-3422.2001

Cited by 119 publications

(119 citation statements)

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“…DISCUSSION CDT is the first bacterial protein toxin found to be seemingly active as a DNase in target mammalian cells (14,15). Previous studies suggest that CDTB is a toxic component and that CDTA and -C are carriers of CDTB to target cells (15,28). Cortes-Bratti et al (29) demonstrated that H. ducreyi CDT was internalized and transported to the Golgi using clathrin-coated pits (29).…”

Section: Figmentioning

confidence: 99%

An N-terminal Segment of the Active Component of the Bacterial Genotoxin Cytolethal Distending Toxin B (CDTB) Directs CDTB into the Nucleus

Nishikubo

Ohara

Ueno

et al. 2003

Journal of Biological Chemistry

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Cytolethal distending toxin (CDT), produced by Actinobacillus actinomycetemcomitans, is a putative virulence factor in the pathogenesis of periodontal diseases. It is a cell cycle specific inhibitor at the G 2 /M transition. CDTB, one of the subunits of the CDT holotoxin, is implicated in a genotoxic role after entering the target cells, whereby chromosomal damage induces checkpoint phosphorylation cascades. CDTB microinjected into the cytoplasm was shown to localize in the nucleus and induce chromatin collapse. To investigate the molecular mechanism involved in nuclear transport of CDTB, we used transient expression and microinjection of a CDTB-green fluorescent protein (GFP) fusion protein. After microinjection, His-tagged CDTB-GFP entered the nucleus in 3-4 h. Leptomycin B did not increase the speed of entry of the fusion protein, suggesting that the relatively slow entry of the fusion protein is not due to the CRM1-dependent nuclear export of the protein. Nuclear localization of the CDTB-GFP was temperature-dependent. An in vitro transport assay demonstrated that the nuclear localization of CDTB is mediated by active transport. An assay using transient expression of a series of truncated CDTB-GFP fusion proteins revealed that residues 48 -124 constitute the minimum region involved in nuclear transport of CDTB. A domain swapping experiment of the region involved in nuclear transport of CDTB with an SV40 T nuclear localization signal indicated that CDTB is composed of two domains, an N-terminal domain for nuclear transport and a C-terminal active domain. Our results strongly suggest that nuclear localization of CDTB is required for the holotoxin to induce cytodistension and cell cycle block. This is the first demonstration that a bacterial toxin possessing a unique domain for nuclear transport is transferred to the animal cell nucleus by active transport.Cytolethal distending toxin (CDT) 1 is a unique bacterial toxin that induces cell cycle arrest of cultured cells in the G 2 phase. It has been identified in several pathogenic bacteria including Campylobacter spp., Escherichia coli, Shigella dysenteriae, Haemophilus ducreyi, Helicobacter hepaticus, and Actinobacillus actinomycetemcomitans. The cells intoxicated with CDT show a cytopathic effect and distension in cell size, and eventually they die, which has been shown to be a common consequence of CDT treated cells (1-4). CDT holotoxin is composed of CDTA, -B, and -C, encoded by the cdtA, cdtB, and cdtC genes tandemly located on the cdt locus (1, 5-7). The CDTinduced G 2 arrest has been ascribed to the inactivation of the Cdc2-cyclin B complex, which is a key molecule for the progression of the cell cycle. In normal cells, dephosphorylation of the Thr-14 and Tyr-15 in Cdc2 triggers G 2 /M transition in the cell cycle. CDT-treated cells were found to maintain Cdc2 with these residues phosphorylated in the Cdc2-cyclin B complex (8). This is because of the recruitment of Cdc25C, a Cdc2-specific phosphatase, from the nucleus to cytoplasm, which prevents dephosphor...

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Section: Figmentioning

confidence: 99%

An N-terminal Segment of the Active Component of the Bacterial Genotoxin Cytolethal Distending Toxin B (CDTB) Directs CDTB into the Nucleus

Nishikubo

Ohara

Ueno

et al. 2003

Journal of Biological Chemistry

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“…CDTs of all strains are composed of three polypeptides (CdtA, CdtB, and CdtC), which form a ternary complex required for the toxin activity (2). Whereas the holotoxin binds to an unknown receptor on the target cell by using CdtA and CdtC subunits, the CdtB subunit enters into the cell to reach the nucleus (2) and causes DNA damage through its DNase I activity (12,13). Therefore, CDT has recently been recognized as a genotoxin (14) and a member of the growing family of bacterial toxins and effectors designated as ''cyclomodulins,'' which interfere with the eukaryotic cell cycle (1).…”

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confidence: 99%

An inducible lambdoid prophage encoding cytolethal distending toxin (Cdt-I) and a type III effector protein in enteropathogenic Escherichia coli

Asakura

Hinenoya

Alam

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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Cytolethal distending toxins (CDTs) are inhibitory cyclomodulins, which block eukaryotic cell proliferation and are produced by a diverse group of Gram-negative bacteria, including Escherichia coli strains associated with intestinal and extraintestinal infections. However, the mode of transmission of the toxin gene clusters among diverse bacterial pathogens is unclear. We found that Cdt-I produced by enteropathogenic E. coli strains associated with diarrhea is encoded by a lambdoid prophage, which is inducible and infectious. The genome of Cdt-I converting phage (CDT-1⌽) comprises 47,021 nucleotides with 60 predicted ORFs organized into six genomic regions encoding the head and tail, virulence, integrase, unknown functions, regulation, and lysis. The genomic organization of CDT-1⌽ is similar to those of SfV, a serotype-converting phage of Shigella flexneri, and UTI89, a prophage identified in uropathogenic E. coli. Besides the cdtI gene cluster, the virulence region of CDT-1⌽ genome contains sequences homologous to a truncated cycle inhibiting factor and a type 3 effector protein. Mutation analysis of susceptible E. coli strain C600 suggested that the outer membrane protein OmpC is a putative receptor for CDT-1⌽. CDT-1⌽ genome was also found to integrate into the host bacterial chromosome forming lysogens, which produced biologically active Cdt-I. Furthermore, phage induction appeared to cause enhanced toxigenicity of the E. coli strains carrying lysogenic CDT-1⌽. Our results suggest that CDT-1⌽ is the latest member of a growing family of lambdoid phages encoding bacterial cyclomodulins and that the phage may have a role in horizontal transfer of these virulence genes.bacterial genotoxin ͉ converting phage ͉ cyclomodulins

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“…A variety of virulence factors has been implicated in uropathogenic E. coli (UPEC) pathogenesis, including the type 1 pilus that mediates attachment and colonization of mucosal surfaces (4), hemolysin that induces calcium waves in urothelial cells (5), cytotoxic necrotizing factor that alters GTPase function (6), and cytolethal distending toxin that induces cell cycle arrest (7,8). In addition to the actions of these virulence factors, the morbidity suffered by UTI patients is due to acute inflammation that results from an innate response (9).…”

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confidence: 99%

Antigen-Specific Responses Accelerate Bacterial Clearance in the Bladder

Thumbikat¹,

Waltenbaugh

Schaeffer³

et al. 2006

The Journal of Immunology

100

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Urinary tract infections (UTIs) cause patient morbidity and have a substantial economic impact. Half of all women will suffer a UTI at least once, and 25% of these women will have recurrent infections. That 75% of previously infected women do not become reinfected strongly suggests a role for an adaptive immune response. The goal of this study was to characterize the adaptive immune responses to uropathogenic Escherichia coli (UPEC), the predominant uropathogen. A novel murine model of UTI reinfection was developed using the prototypic cystitis UPEC isolate NU14 harboring a plasmid encoding OVA as a unique antigenic marker. Bacterial colonization of the bladder was quantified following one or more infections with NU14-OVA. Animals developed anti-OVA serum IgG and IgM titers after the initial infection and marked up-regulation of activation markers on splenic T cells. We observed a 95% reduction in bacterial colonization upon reinfection, and splenic leukocytes showed Ag-specific proliferation in vitro. Adoptive transfer of splenic T cells or passive transfer of serum from previously infected mice protected naive syngeneic mice from UPEC colonization. These findings support our hypothesis that adaptive immune responses to UPEC protect the bladder from reinfection and form the basis of understanding susceptibility to recurrent UTI in women.

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Escherichia coliCdtB Mediates Cytolethal Distending Toxin Cell Cycle Arrest

Cited by 119 publications

References 21 publications

An N-terminal Segment of the Active Component of the Bacterial Genotoxin Cytolethal Distending Toxin B (CDTB) Directs CDTB into the Nucleus

An N-terminal Segment of the Active Component of the Bacterial Genotoxin Cytolethal Distending Toxin B (CDTB) Directs CDTB into the Nucleus

An inducible lambdoid prophage encoding cytolethal distending toxin (Cdt-I) and a type III effector protein in enteropathogenic Escherichia coli

Antigen-Specific Responses Accelerate Bacterial Clearance in the Bladder

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