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6  structures 170  species 2  interactions 430  sequences 1  architecture

Family: CDtoxinA (PF03498)

Summary: Cytolethal distending toxin A/C family

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Cytolethal distending toxin Edit Wikipedia article

Cytolethal distending toxin
PDB protein 1sr4 (HdCDT).jpg
Crystal structure of the fully assembled Haemophilus ducreyi cytolethal distending toxin
Identifiers
Symbol CDT
Pfam PF03498
Pfam clan CL0066
InterPro IPR003558

Cytolethal distending toxins (abbreviated CDTs) are a class of heterotrimeric toxins produced by certain gram-negative bacteria that display DNase activity.[1][2] These toxins trigger G2/M cell cycle arrest in specific mammalian cell lines, leading to the enlarged or distended cells for which these toxins are named.[3] Affected cells die by apoptosis.[1]

Each toxin consists of three distinct subunits named alphabetically in the order that their coding genes appear in the cdt operon. Cytolethal distending toxins are classified as AB toxins, with an active ("A") subunit which directly damages DNA and a binding ("B") subunit that helps the toxin attach to the target cells. CdtB is the active subunit and a homolog to mammalian DNase I while CdtA and CdtC make up the binding subunit.[4]

Cytolethal distending toxins are produced by gram-negative pathogenic bacteria from the phylum Proteobacteria. Many of these bacteria, including Shigella dysenteriae, Haemophilus ducreyi, and Escherichia coli, infect humans. Bacteria that produce CDTs often persistently colonize their host.[1]

History[edit]

The first recorded observation of a cytolethal-distending toxin was in 1987 in a pathogenic strain in E. coli isolated from a young patient.[3] Later that year, scientists W.M. Johnson and H. Lior published the journal article “Production of Shiga toxin and a cytolethal distending toxin (CLDT) by serogroups of Shigella spp.” In Microbiology Letters.[1] The discovery of other bacteria producing CDT toxins continues to this day.

In 1994 two scientists, Scott and Kaper, successfully cloned and sequenced a cdt operon from another E. coli strain, publishing their accomplishment in Infection and Immunity.[1][5] The three genes discovered were denoted cdtA, cdtB, and cdtC.[5]

In 1997, the first paper of many to show G2/M cell cycle arrest caused by a cytolethal distending toxin was published in Molecular Microbiology.[1] The study focused on another E. coli strain. This paper was followed by a 1999 publication in Infectious Immunity which demonstrated that H. ducreyi CDT causes cell death via apoptosis. This finding was also confirmed for other cytolethal distending toxins in subsequent studies.

The discovery of the homology of cdtB to mammalian DNase I and the current AB model for the toxin were published in early 2000. [2][6] Further research and the publication of crystal structures for the CDT toxins from two different species continues to support this model.[1]

Sources[edit]

All known cytolethal distending toxins are produced by gram-negative bacteria in the gamma and epsilon classes of the Proteobacteria phylum. In several cases, the bacteria producing CDT are human pathogens. Medically important CDT producers include:[1]

CDT-producing bacteria are often associated with mucosal linings, such as those in the stomach and intestines, and with persistent infections. The toxins are either secreted freely or associated with the membrane of the producing bacteria.[1]

Nomenclature[edit]

Individual cytolethal distending toxins are named for the bacterial species that they are isolated from. As of 2011, most scientists have adopted the practice of placing the first letter of both the genus and species in front of the toxin name to reflect its source (i.e. the CDT from Haemaphilus ducreyi is referred to as HdCDT).[1][7] If several subspecies produce different toxins, as in the case of E. coli, Roman numerals may be added after the second letter.[7] Both complete toxins and individual subunits are labeled using this convention.

In response to the continued discovery of additional cytolethal distending toxins, a 2011 review has proposed that the toxin names be expanded to include the first three letters of the species (i.e. HducCDT for Haemaphilus ducreyi CDT).[1]

Cellular Effects[edit]

CDT toxins are genotoxins capable of directly damaging DNA in target cells. They are the only AB-type toxins discovered that display DNase activity, allowing them to introduce breaks into the target cell's DNA.[1][4]

In many cell lines including human fibroblasts, epithelial cells, endothelial cells, and keratinocytes, CDTs cause G2/M cell cycle arrest, cytoplasmic distension, and eventual cell death via apoptosis.[1][3][8] Most publications attribute the G2/M cycle arrest to the buildup of irreversible DNA damage from the toxin’s DNase activity as the trigger for the G2/M cell cycle arrest, but other research suggests that this model is incomplete.[8] The cytoplasmic distension is a direct result of the G2/M cell cycle arrest. The cell enlarges in preparation for mitosis, but cannot divide to restore its normal size. Aside from classical apoptosis, signs of cellular senescence has also been observed in normal and cancer cell lines (fibroblasts, HeLa and U2-OS) after CDT intoxication[9]

In lymphocytes, cell death occurs quickly and is not preceded by significant cytoplasmic distension.[8] The ability of theses toxins to effect lymphocytes differently may be advantageous to the bacteria that utilize these toxins, but the mechanism behind this phenomena is not yet well understood.

Toxin Structure[edit]

The active, assembled toxin is a tripartite structure with three distinct subunits- CdtA, CdtB, and CdtC. Functionally, it is an AB toxin. In this context, the CdtB subunit is actually the catalytically active "A" subunit, and the CdtA and CdtC together form the binding "B" subunit which helps the toxin bind and enter target cells.[6] Some literature refers to the toxin structure as AB2 to reflect the presence of both CdtA and CdtC.

Differently from all other CDTs, Salmonella enterica serovar Typhi CDT (SeCDT) has no CdtA and CdtC homologues. However, encoded closely to the active subunit cdtb, the Pertussis-like toxin A and B (pltA/pltB) have been shown to be essential for cellular intoxication.[10] PltA and PltB have a different structure from CdtA and CdtC, thus promoting CdtB activity in a different way. Both PltA and PltB have been found to bind directly to CdtB in vitro.[10] Additionally, differently from all other CDTs, Salmonella genotoxin is produced only upon bacterial internalization in infected cells, thus the SeCDT traffic may differ remarkably from the canonical ones.

CdtB[edit]

CdtB is considered the active subunit of the CDT holotoxin. Microinjection of CdtB into susceptible cells without CdtA or CdtC results in the G2/M cell cycle arrest and cytoplasmic distension characteristic of CDT toxins.[2] The structure of CdtB is well conserved between different bacteria. The CdtB subunit is the most sequentially conserved between species.[4] The molecular weight of CdtB ranges from 28 kDa to 29 kDa, depending on the species.[1]

As the active subunit, CdtB is termed the "A" subunit according to the AB toxin model.[1] This confusing nomenclature is due to the toxin’s subunits being named before their individual functions were understood.

Activity[edit]

CdtB exhibits at least two enzymatic activities- DNase activity capable of introducing double-stranded breaks in DNA, and a phosphatase activity that resembles phosphatidylinositol 3,4,5-triphosphatase.[2][8] Both activities can be demonstrated in vitro in the absence of the other two subunits.[11] The relative importance of each activity in vivo is unclear.[11] Mutations that reduce either activity also reduce the toxin’s ability to induce G2/M phase arrest in at least some of the susceptible cell lines.[2][8]

Similarities to mammalian DNase I[edit]

CdtB is functionally homologous to mammalian DNase I and contains a conserved pentapeptide sequence found in all DNase I enzymes to date.[2] In addition, several residues critical to DNase I’s ability to break the phosphodiester bonds in the DNA backbone are found in the CdtB structure. A 2002 paper studying the effect of point mutations on five of these residues found that four of the five mutations tested abolished both CdtB’s ability to degrade DNA in cell-free extracts and to cause G2/M arrest upon microinjection. The fifth mutation moderately reduced CdtB’s activity.[2]

CdtA and CdtC[edit]

CdtA and CdtC make up the B subunit of the CDT holotoxin responsible for targeting the CdtB against susceptible cells.[6] Neither subunit appears highly conserved, with sequence identities between different species often lower than 30%.[4] The molecular weight of CdtA ranges from 23 kDa to 30 kDa, while CdtC ranges from 19 kDa to 21 kDa depending on the species.[1]

Activity[edit]

CdtA and CdtC are both believed to bind to the surface of target cells. The exact mechanism of this binding is unclear, and may not be conserved between CDT toxins from different species.[1][11] Proposed targets of CdtA and CdtC binding have included cholesterol, N-linked glycans, and glycosphingolipids.[11] Current research has produced conflicting results on the actual importance of these proposed targets.[1][11] Both CdtA and CdtC contain lectin domains,[12] suggesting that the toxin may bind via carbohydrates on the target cell’s surface, while other research has suggested that the targets are surface proteins.[1]

Notes[edit]

  1. ^ a b c d e f g h i j k l m n o p q r s Rasika N.Jindasa, Stephen E. Bloom, Robert S. Weiss,Gerald E. Duhamel. (2011). "Cytolethal distending toxin: a conserved bacterial genotoxin that blocks cell cycle progression, leading to apoptosis of a broad range of mammalian cell lineages.". Microbiology 157 (7): 1851–1875. 
  2. ^ a b c d e f g Cherilyn A. Elwell, Lawrence A. Dreyfus (2000). "DNase I homologous residues in CdtB are critical for cytolethal distending toxin-mediated cell cycle arrest.". Molecular Microbiology 37 (4): 952–963. doi:10.1046/j.1365-2958.2000.02070.x. 
  3. ^ a b c Dreyfus, Lawrence, A. (2003), "Cyotlethal Distending Toxin", in D. Burns et al., Bacterial Protein Toxins, Washington, DC: ASM Press, pp. 257–270  Unknown parameter |title-url= ignored (help)
  4. ^ a b c d Lina Guerra, Ximena Cortes-Bratti, Riccardo Guidi, Teresa Frisan (2011). "The Biology of Cytolethal Distending Toxins". Toxins 3 (3): 172–190. 
  5. ^ a b D A Scott and J B Kaper (1994). "Cloning and sequencing of the Escherichia coli cytolethal distending toxin.". Infection and Immunity 62 (1): 244–251. 
  6. ^ a b c Maria Lara-Tejero, Jorge E. Galan. (2001). "CdtA, CdtB, and CdtC Form a Tripartite Complex That Is Required for Cytolethal Distending Toxin Activity". Infectious Immunity 69 (7): 4358–4365. doi:10.1128/IAI.69.7.4358-4365.2001. PMC 98507. PMID 11401974. 
  7. ^ a b Cortes-Bratti, Teresa Frisan, Monica Thelestam. (2001). "The Cytolethal Distending Toxins Induce DNA Damage and Cell Cycle Arrest.". Toxicon 39 (11): 1729–1736. doi:10.1016/S0041-0101(01)00159-3. 
  8. ^ a b c d e Bruce J. Shenker, Mensur Dlakic, Lisa P. Walker, Dave Besack, Eileen Jaffe, Ed LaBelle, Kathleen Boesze-Battaglia. (2007). "A Novel Mode of Action for a Microbial-Derived Immunotoxin: The Cytolethal Distending Toxin Subunit B Exhibits Phosphatidylinositol 3,4,5-Triphosphate Phosphatase Activity". The Journal of Immunology 178 (8): 5099–5108. 
  9. ^ Blazkova, Hana; Krejcikova, Katerina; Moudry, Pavel; Frisan, Teresa; Hodny, Zdenek; Bartek, Jiri (1 January 2010). "Bacterial intoxication evokes cellular senescence with persistent DNA damage and cytokine signalling". Journal of Cellular and Molecular Medicine 14 (1-2): 357–367. doi:10.1111/j.1582-4934.2009.00862.x. 
  10. ^ a b Spanò, Stefania; Ugalde, Juan E.; Galán, Jorge E. (31 December 2007). "Delivery of a Salmonella Typhi Exotoxin from a Host Intracellular Compartment". Cell Host & Microbe 3 (1): 30–38. doi:10.1016/j.chom.2007.11.001. 
  11. ^ a b c d e Aria Eshraghi, Francisco J. Maldonado-Arocho, Amandeep Gargi, Marissa M. Cardwell, Michael G. Prouty, Steven R. Blanke, and Kenneth A. Bradley. (2010). "Cytolethal Distending Toxin Family Members are Differentially Affected by Alterations in Host Glycans and Membrane Cholesterol". The Journal of Biological Chemistry 285 (24): 18199–18207. 
  12. ^ Dragana Nesic, Yun Hsu, C. Erec Stebbins. (2004). "Assembly and Function of A Bacterial Genotoxin.". Nature 429 (6990): 429–433. doi:10.1038/nature02532. 

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Cytolethal distending toxin A/C family Provide feedback

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InterPro entry IPR003558

Escherichia coli, Haemophilus spp and Campylobacter spp. all produce a toxin that is seen to cause distension in certain cell lines [PUBMED:8112838, PUBMED:10203548], which eventually disintegrate and die. This novel toxin, termed cytolethal distending toxin (cdt), has three subunits: A, B and C. Their sizes are approx. 27.7, 29.5 and 19.9kDa respectively [PUBMED:8112838], and they appear to be entirely novel [PUBMED:10203548].

Further research on the complete toxin has revealed that it blocks the cell cycle at stage G2, through inactivation of the cyclin-dependent kinase Cdk1, and without induction of DNA breaks. This leads to multipolar abortive mitosis and micronucleation, associated with centrosomal amplification [PUBMED:10777111]. The roles of each subunit are unclear, but it is believed that they have separate roles in pathogenicity.

This entry represents the A and C subunits.

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Seed source: PRINTS
Previous IDs: none
Type: Family
Author: Griffiths-Jones SR, Bateman A
Number in seed: 10
Number in full: 430
Average length of the domain: 145.30 aa
Average identity of full alignment: 32 %
Average coverage of the sequence by the domain: 69.60 %

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Parameter Sequence Domain
Gathering cut-off 21.6 21.6
Trusted cut-off 21.7 21.9
Noise cut-off 21.5 21.5
Model length: 150
Family (HMM) version: 9
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Exo_endo_phos CDtoxinA

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