Binary Actin-ADP-Ribosylating Toxins and their Use as Molecular Trojan Horses for Drug Delivery into Eukaryotic Cells

Barth, Holger; Stiles, Bradley G.

doi:10.2174/092986708783503195

Cited by 52 publications

(71 citation statements)

References 51 publications

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“…Mature IA consists of an N-terminal domain that interacts with IB and a C-terminal domain with ADP-ribosyltransferase activity. Mature IB exhibits some similarity with Bacillus anthracis protective antigen (PA) but not in the receptor binding domain, which is consistent with IB and PA recognizing different receptors (115)(116)(117)(118). IB has four domains, which mediate (i) IA interactions, (ii) internalization into host cells, (iii) oligomerization, and (iv) binding to host cell receptors (115)(116)(117)(118).…”

Section: Plasmid-encoded Toxinsmentioning

confidence: 69%

“…Iota-toxin (ITX) is a member of the clostridial binary toxin family and consists of separate IA and IB proteins that are produced as proproteins and then proteolytically activated when their N-terminal sequences are removed by host proteases (e.g., chymotrypsin) or C. perfringens lambda-toxin (115)(116)(117)(118). Mature IA consists of an N-terminal domain that interacts with IB and a C-terminal domain with ADP-ribosyltransferase activity.…”

Section: Plasmid-encoded Toxinsmentioning

confidence: 99%

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Toxin Plasmids of Clostridium perfringens

Adams

Bannam

et al. 2013

Microbiol Mol Biol Rev

226

282

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SUMMARY In both humans and animals, Clostridium perfringens is an important cause of histotoxic infections and diseases originating in the intestines, such as enteritis and enterotoxemia. The virulence of this Gram-positive, anaerobic bacterium is heavily dependent upon its prolific toxin-producing ability. Many of the ∼16 toxins produced by C. perfringens are encoded by large plasmids that range in size from ∼45 kb to ∼140 kb. These plasmid-encoded toxins are often closely associated with mobile elements. A C. perfringens strain can carry up to three different toxin plasmids, with a single plasmid carrying up to three distinct toxin genes. Molecular Koch's postulate analyses have established the importance of several plasmid-encoded toxins when C. perfringens disease strains cause enteritis or enterotoxemias. Many toxin plasmids are closely related, suggesting a common evolutionary origin. In particular, most toxin plasmids and some antibiotic resistance plasmids of C. perfringens share an ∼35-kb region containing a Tn 916 -related conjugation locus named tcp (transfer of clostridial plasmids). This tcp locus can mediate highly efficient conjugative transfer of these toxin or resistance plasmids. For example, conjugative transfer of a toxin plasmid from an infecting strain to C. perfringens normal intestinal flora strains may help to amplify and prolong an infection. Therefore, the presence of toxin genes on conjugative plasmids, particularly in association with insertion sequences that may mobilize these toxin genes, likely provides C. perfringens with considerable virulence plasticity and adaptability when it causes diseases originating in the gastrointestinal tract.

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Section: Plasmid-encoded Toxinsmentioning

confidence: 69%

Section: Plasmid-encoded Toxinsmentioning

confidence: 99%

Toxin Plasmids of Clostridium perfringens

Adams

Bannam

et al. 2013

Microbiol Mol Biol Rev

226

282

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“…The C2 toxin of Clostridium botulinum belongs to the family of binary bacterial AB-type toxins, consisting of the two separate proteins C2I and C2II (Barth and Stiles 2008). The enzymatically active C2I component exhibits mono-ADP-ribosyltransferase activity and catalyzes the modification of actin upon cell entry (Aktories et al 1986).…”

Section: Introductionmentioning

confidence: 99%

Internalization of biotinylated compounds into cancer cells is promoted by a molecular Trojan horse based upon core streptavidin and clostridial C2 toxin

Fahrer

Funk

Lillich

et al. 2010

Naunyn-Schmied Arch Pharmacol

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The C2 toxin produced by Clostridium botulinum is a binary AB-type exotoxin composed of the enzyme subunit C2I and the binding/translocation moiety C2II. After proteolytic activation, C2IIa mediates the subsequent internalization of C2I into the cytosol of mammalian target cells. The N-terminal domain of C2I (C2IN) is necessary for C2IIa-dependent uptake, but lacks the enzyme domain that is responsible for cytotoxicity. In the present study, we generated a delivery system building on C2IN and a truncated core streptavidin (Stv13) with enhanced solubility for the C2IIa-dependent internalization of biotinylated cargo molecules into mammalian cells. C2IN-Stv13 fusion protein expressed in Escherichia coli was obtained in high yields and purity. The affinity-purified protein formed tetramers and a defined higher order species in solution as shown by gel filtration and retained its biotin-binding properties, however with an obvious reduction in affinity. Uptake of C2IN-Stv13 into the cytosol of HeLa and other cancer cell lines was observed by immunoblot analysis, which was corroborated by confocal microscopy. In addition, the fusion protein was not cytotoxic and did not inhibit cell proliferation as determined by MTS assay. Finally, we demonstrated the C2IN-Stv13/C2IIa-mediated uptake of biocytin-Alexa 488 as cargo into HeLa cells, underscoring the functionality of the generated transport system.

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“…Essential properties of the toxins and their corresponding genes have been reviewed in the past [1]. Each toxin is produced as two unrelated separate gene products, one an enzyme, the other a cell-binding / membrane translocation factor.…”

Section: Introductionmentioning

confidence: 99%

“…Exogenous trypsin is required for the activation of pro-CDTb [2]. Mature binding component rapidly oligomerizes on the surface of a target cell to form a heptameric, donut-shaped channel through which the enzyme enters the cell (following endosome acidification) and mono-ADP-ribosylates globular actin, thus killing the cell by disrupting its cytoskeleton and particularly filamentous actin formation [1,3]. Neither component by itself has toxic activity, though individually each retains its respective binding and enzymatic properties.…”

Section: Introductionmentioning

confidence: 99%

Iota Toxin, S Toxin and CDT: Members of the Same Class of Clostridial Binary Toxins in Feces of Humans and Other Animals

Carman¹

2013

TOTNJ

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Some strains of Clostridium perfringens, Clostridium spiroforme and Clostridium difficile produce binary toxins known respectively as iota toxin, S toxin and CDT. Each toxin consists of two unlinked polypeptides (e.g. CDTa and CDTb) that only together have biological activity. Taking an historical perspective, we review the development and early use of assays employing the specific neutralization of a biological activity for the detection and quantification of binary toxin. The survey moves on to more recent immunological assays and culminates with a discussion of the relevance of binary toxin, especially CDT, in feces.

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Binary Actin-ADP-Ribosylating Toxins and their Use as Molecular Trojan Horses for Drug Delivery into Eukaryotic Cells

Cited by 52 publications

References 51 publications

Toxin Plasmids of Clostridium perfringens

Toxin Plasmids of Clostridium perfringens

Internalization of biotinylated compounds into cancer cells is promoted by a molecular Trojan horse based upon core streptavidin and clostridial C2 toxin

Iota Toxin, S Toxin and CDT: Members of the Same Class of Clostridial Binary Toxins in Feces of Humans and Other Animals

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