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EcoSal Plus

Domain 8:

Pathogenesis

The Enterobacterial Genotoxins: Cytolethal Distending Toxin and Colibactin

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  • Authors: Frederic Taieb1, Claude Petit2, Jean-Philippe Nougayrède3, and Eric Oswald4
  • Editor: Michael S. Donnenberg5
  • VIEW AFFILIATIONS HIDE AFFILIATIONS
    Affiliations: 1: Institut de Recherche en Santé Digestive (IRSD), INRA UMR1416, INSERM U1220, Université de Toulouse, CHU Purpan, Toulouse, FRANCE; 2: Institut de Recherche en Santé Digestive (IRSD), INRA UMR1416, INSERM U1220, Université de Toulouse, CHU Purpan, Toulouse, FRANCE; 3: Institut de Recherche en Santé Digestive (IRSD), INRA UMR1416, INSERM U1220, Université de Toulouse, CHU Purpan, Toulouse, FRANCE; 4: Institut de Recherche en Santé Digestive (IRSD), INRA UMR1416, INSERM U1220, Université de Toulouse, CHU Purpan, Toulouse, FRANCE; 5: University of Maryland, School of Medicine, Baltimore, MD
  • Received 21 March 2016 Accepted 22 April 2016 Published 14 July 2016
  • Address correspondence to Eric Oswald: eric.oswald@inserm.fr
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  • Abstract:

    While the DNA damage induced by ionizing radiation and by many chemical compounds and drugs is well characterized, the genotoxic insults inflicted by bacteria are only scarcely documented. However, accumulating evidence indicates that we are exposed to bacterial genotoxins. The prototypes of such bacterial genotoxins are the Cytolethal Distending Toxins (CDTs) produced by and serovar Typhi. CDTs display the DNase structure fold and activity, and induce DNA strand breaks in the intoxicated host cell nuclei. and certain other species synthesize another genotoxin, colibactin. Colibactin is a secondary metabolite, a hybrid polyketide/nonribosomal peptide compound synthesized by a complex biosynthetic machinery. In this review, we summarize the current knowledge on CDT and colibactin produced by and/or Typhi. We describe their prevalence, genetic determinants, modes of action, and impact in infectious diseases or gut colonization, and discuss the possible involvement of these genotoxigenic bacteria in cancer.

  • Citation: Taieb F, Petit C, Nougayrède J, Oswald E. 2016. The Enterobacterial Genotoxins: Cytolethal Distending Toxin and Colibactin, EcoSal Plus 2016; doi:10.1128/ecosalplus.ESP-0008-2016

Key Concept Ranking

Mobile Genetic Elements
0.76103044
Cytolethal Distending Toxin
0.44062498
Type VI Secretion System
0.43236154
0.76103044

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ecosalplus.ESP-0008-2016.citations
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/content/journal/ecosalplus/10.1128/ecosalplus.ESP-0008-2016
2016-07-14
2017-05-29

Abstract:

While the DNA damage induced by ionizing radiation and by many chemical compounds and drugs is well characterized, the genotoxic insults inflicted by bacteria are only scarcely documented. However, accumulating evidence indicates that we are exposed to bacterial genotoxins. The prototypes of such bacterial genotoxins are the Cytolethal Distending Toxins (CDTs) produced by and serovar Typhi. CDTs display the DNase structure fold and activity, and induce DNA strand breaks in the intoxicated host cell nuclei. and certain other species synthesize another genotoxin, colibactin. Colibactin is a secondary metabolite, a hybrid polyketide/nonribosomal peptide compound synthesized by a complex biosynthetic machinery. In this review, we summarize the current knowledge on CDT and colibactin produced by and/or Typhi. We describe their prevalence, genetic determinants, modes of action, and impact in infectious diseases or gut colonization, and discuss the possible involvement of these genotoxigenic bacteria in cancer.

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Figures

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Figure 1

HeLa cells were treated with purified CDT (CDTwt) or with CDT mutated on CdtB-conserved histidine (H153A) (CDTm) or infected with producing or not colibactin ( pks+ and pks–). Cells were stained with methylene blue 3 days after the treatment. Bar represents 100 µm.

Citation: Taieb F, Petit C, Nougayrède J, Oswald E. 2016. The Enterobacterial Genotoxins: Cytolethal Distending Toxin and Colibactin, EcoSal Plus 2016; doi:10.1128/ecosalplus.ESP-0008-2016
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Figure 2

(A) Percent identity matrix of CdtB subunits of (type I to V), , , , , and Typhi; identity score >89% are shown in bold. (B) Phylogenetic tree of CdtB subunits, with real branch length. Brackets indicate an identity score >89%. (C) Percent identity matrix of CdtA and CdtC subunits; identity score >84% are shown in bold.

Citation: Taieb F, Petit C, Nougayrède J, Oswald E. 2016. The Enterobacterial Genotoxins: Cytolethal Distending Toxin and Colibactin, EcoSal Plus 2016; doi:10.1128/ecosalplus.ESP-0008-2016
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Figure 3

In , , , , and , the CDT operon contains 3 genes that synthetize the 3 subunits CdtA (red), CdtB (green), and CdtC (blue) that are translocated and assembled in the periplasm. Following secretion, CDT binds to a nonidentified receptor on the host eukaryotic cell. Following internalization, CdtB is retrotransported through the Golgi apparatus. Through an ERAD-like pathway, CdtB reaches the nucleus and host DNA. Alternatively, CDT is trapped in OMVs that can deliver the toxin into the host cell by fusion with the plasma membrane or through binding to a receptor. . Typhi is an intracellular pathogen remaining in the cytosol in the -containing vacuole (SCV). CdtB is encoded on a CdtB islet (or SPI-11) together with (fuchsia) and (orange). These gene products form the typhoid toxin that contains 2 “active” subunits (CdtB and PltA) and a pentameric “binding” subunit (PltB). The toxin might be entrapped in OMVs and secreted through vacuoles that exit from the SCV and intoxicates cells through autocrine and paracrine pathways. ERAD, endoplasmic reticulum-associated degradation; OMV, outer membrane vesicle; SPI, pathogenicity island; plt, pertussis-like toxin).

Citation: Taieb F, Petit C, Nougayrède J, Oswald E. 2016. The Enterobacterial Genotoxins: Cytolethal Distending Toxin and Colibactin, EcoSal Plus 2016; doi:10.1128/ecosalplus.ESP-0008-2016
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Figure 4

CdtB (Protein Data Bank [PDB] 2F1N, light blue), Typhi CdtB (PDB 4K6L, purple) aligned with DNase I (light grey) complexed with target DNA (PDB 1DNK, green). The main catalytic residues D211, H136, and H243 are highlighted in red.

Citation: Taieb F, Petit C, Nougayrède J, Oswald E. 2016. The Enterobacterial Genotoxins: Cytolethal Distending Toxin and Colibactin, EcoSal Plus 2016; doi:10.1128/ecosalplus.ESP-0008-2016
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Figure 5

Genotoxin-induced DNA double-strand breaks activate ATM/ATR, resulting in phosphorylation of H2AX (γH2AX in magenta), checkpoint protein kinase (CHK) recruitment, activation of DNA repair machineries, and ultimately apoptosis and senescence. Cell cycle arrest results from nuclear exclusion of the phosphatase CDC25 and accumulation of CDK inhibitor p21. Cytoplasmic CDC25 cannot relieve the cyclin-dependent kinase (CDK) from its inhibitory phosphorylation, and CDK-cyclin complexes are further inhibited by p21. Since activation of CDK-cyclin is required for cell cycle progression, activation of the DDR results in cell cycle arrest. In the case of incomplete DNA repair following a chronic or low level of genotoxin exposure, cells accumulate mutations and develop genomic instability.

Citation: Taieb F, Petit C, Nougayrède J, Oswald E. 2016. The Enterobacterial Genotoxins: Cytolethal Distending Toxin and Colibactin, EcoSal Plus 2016; doi:10.1128/ecosalplus.ESP-0008-2016
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Figure 6

The genomic island contains 19 genes ( to ) encoding polyketide synthases (PKS, orange), nonribosomal peptide synthases (NRPS red), hybrid PKS-NRPS (orange/red) and genes with unknown function (black). Other “accessory” enzymes and proteins are encoded by (phosphopantetheinyl transferase), (efflux pump), (peptidase) and (resistance protein).

Citation: Taieb F, Petit C, Nougayrède J, Oswald E. 2016. The Enterobacterial Genotoxins: Cytolethal Distending Toxin and Colibactin, EcoSal Plus 2016; doi:10.1128/ecosalplus.ESP-0008-2016
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Figure 7

The NRPS-PKS assembly line is posttranslationally matured with a 4′-phosphopantetheine (PP) arm on the carrier proteins by the ClbA PP transferase. The active assembly line synthesizes precolibactin that is translocated in the periplasm by the ClbM efflux pump. The prodrug is cleaved by the ClbP peptidase to generate the cleavage product (black) and active mature colibactin (red). Self-damage to the producing bacterium DNA by active colibactin is prevented by the periplasmic maturation and by the cytoplasmic ClbS resistance protein.

Citation: Taieb F, Petit C, Nougayrède J, Oswald E. 2016. The Enterobacterial Genotoxins: Cytolethal Distending Toxin and Colibactin, EcoSal Plus 2016; doi:10.1128/ecosalplus.ESP-0008-2016
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Figure 8

Cleavage product released by the ClbP peptidase (1) and precolibactins molecules (2 and 3) that were elucidated in mutants, based on mass spectrometry and nuclear magnetic resonance data. The electrophilic warhead, putative DNA intercalating motif, and the peptidase cleavage site are shown.

Citation: Taieb F, Petit C, Nougayrède J, Oswald E. 2016. The Enterobacterial Genotoxins: Cytolethal Distending Toxin and Colibactin, EcoSal Plus 2016; doi:10.1128/ecosalplus.ESP-0008-2016
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Tables

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Table 1

Comparative key characteristics of CDT, typhoid toxin, and colibactin

Citation: Taieb F, Petit C, Nougayrède J, Oswald E. 2016. The Enterobacterial Genotoxins: Cytolethal Distending Toxin and Colibactin, EcoSal Plus 2016; doi:10.1128/ecosalplus.ESP-0008-2016

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