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The cell cycle-specific growth-inhibitory factor produced by Actinobacillus actinomycetemcomitans is a cytolethal distending toxin.

ABSTRACT: Actinobacillus actinomycetemcomitans has been shown to produce a soluble cytotoxic factor(s) distinct from leukotoxin. We have identified in A. actinomycetemcomitans Y4 a cluster of genes encoding a cytolethal distending toxin (CDT). This new member of the CDT family is similar to the CDT produced by Haemophilus ducreyi. The CDT from A. actinomycetemcomitans was produced in Escherichia coli and was able to induce cell distension, growth arrest in G2/M phase, nucleus swelling, and chromatin fragmentation in HeLa cells. The three proteins, CDTA, -B and -C, encoded by the cdt locus were all required for toxin activity. Antiserum raised against recombinant CDTC completely inhibited the cytotoxic activity of culture supernatant and cell homogenate fractions of A. actinomycetemcomitans Y4. These results strongly suggest that the CDT is responsible for the cytotoxic activity present in the culture supernatant and cell homogenate fractions of A. actinomycetemcomitans Y4. This CDT is a new putative virulence factor of A. actinomycetemcomitans and may play a role in the pathogenesis of periodontal diseases.

SUBMITTER: Sugai M

PROVIDER: S-EPMC108622 | biostudies-literature | 1998 Oct

REPOSITORIES: biostudies-literature

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The cell cycle-specific growth-inhibitory factor produced by Actinobacillus actinomycetemcomitans is a cytolethal distending toxin.

Sugai M M Kawamoto T T Pérès S Y SY Ueno Y Y Komatsuzawa H H Fujiwara T T Kurihara H H Suginaka H H Oswald E E

Infection and immunity 19981001 10

Actinobacillus actinomycetemcomitans has been shown to produce a soluble cytotoxic factor(s) distinct from leukotoxin. We have identified in A. actinomycetemcomitans Y4 a cluster of genes encoding a cytolethal distending toxin (CDT). This new member of the CDT family is similar to the CDT produced by Haemophilus ducreyi. The CDT from A. actinomycetemcomitans was produced in Escherichia coli and was able to induce cell distension, growth arrest in G2/M phase, nucleus swelling, and chromatin fragm ...[more]

PMID: 9746611

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Project description:The cytolethal distending toxin (Cdt) of Actinobacillus actinomycetemcomitans is an atypical A-B-type toxin consisting of a heterotrimer composed of the cdtA, cdtB, and cdtC gene products. The CdtA and CdtC subunits form two heterogeneous ricin-like lectin domains which bind the holotoxin to the target cell. Point mutations were used to study CdtC structure and function. One (mutC216(F97C)) of eight single-amino-acid replacement mutants identified yielded a gene product that failed to form biologically active holotoxin. Based on the possibility that the F97C mutation destabilized a predicted disulfide, targeted mutagenesis was used to examine the contribution of each of four cysteine residues, in two predicted disulfides (C96/C107 and C135/C149), to CdtC activities. Cysteine replacement mutations in two predicted disulfides (C136/C149 and C178/C197) in CdtA were also characterized. Flow cytometry and CHO cell proliferation assays showed that changing either C96 or C149 in CdtC to alanine abolished the biological activity of holotoxin complexes. However, replacing C107 or C135 in CdtC and any of the four cysteines in CdtA with alanine or serine resulted in only partial or no loss of holotoxin activity. Changes in the biological activities of the mutant holotoxins correlated with altered subunit binding. In contrast to elimination of the B chain of ricin, the elimination of intrachain disulfides in CdtC and CdtA by genetic replacement of cysteines destabilizes these subunit proteins but not to the extent that cytotoxicity is lost. Reduction of the wild-type holotoxin did not affect cytotoxicity, and the reduced form of wild-type CdtA exhibited a statistically significant increase in binding to ligand. A diminished role for intrachain disulfides in stabilizing CdtA and CdtC may have clinical relevance for the A. actinomycetemcomitans Cdt. The cdt gene products secreted by this pathogen assemble and bind to target cells in periodontally involved sites, which are decidedly reduced environments in the human oral cavity.

Dataset Information

The cell cycle-specific growth-inhibitory factor produced by Actinobacillus actinomycetemcomitans is a cytolethal distending toxin.

Publications

The cell cycle-specific growth-inhibitory factor produced by Actinobacillus actinomycetemcomitans is a cytolethal distending toxin.

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