CdtA, CdtB, and CdtC Form a Tripartite Complex That is Required for Cytolethal Distending Toxin Activity

Overview

Journal Infect Immun

Publisher American Society for Microbiology

Specialty Allergy & Immunology

Date 2001 Jun 13

PMID 11401974

Citations 127

Authors

M Lara-Tejero

J E Galan

Affiliations

Soon will be listed here.

Abstract

Campylobacter jejuni encodes a cytolethal distending toxin (CDT) that causes cells to arrest in the G(2)/M transition phase of the cell cycle. Highly related toxins are also produced by other important bacterial pathogens. CDT activity requires the function of three genes: cdtA, cdtB, and cdtC. Recent studies have established that CdtB is the active subunit of CDT, exerting its effect as a nuclease that damages the DNA and triggers cell cycle arrest. Microinjection of CdtB into target cells led to G(2)/M arrest and cytoplasmic distention, in a manner indistinguishable from that caused by CDT treatment. Despite this progress, nothing is known about the composition of the CDT holotoxin or the function of CdtA and CdtC. We show here that, when applied individually, purified CdtA, CdtB, or CdtC does not exhibit toxic activity. In contrast, CdtA, CdtB, and CdtC when combined, interact with one another to form an active tripartite holotoxin that exhibits full cellular toxicity. CdtA has a domain that shares similarity with the B chain of ricin-related toxins. We therefore proposed that CDT is a tripartite toxin composed of CdtB as the enzymatically active subunit and of CdtA and CdtC as the heterodimeric B subunit required for the delivery of CdtB.

Citing Articles

Prevalence and genetic characteristics of Campylobacter jejuni from laying-hens in Hubei Province, China.

Kuang S, Wang Z, Hu X, Dong Z, Wang C, Xiao Y BMC Vet Res. 2025; 21(1):84.

PMID: 39987068 PMC: 11846460. DOI: 10.1186/s12917-025-04600-7.

Cytolethal distending toxin-producing Escherichia coli clinical isolates from Mexican children harbor different cdt types causing CDT-induced epithelial pathological phenotypes.

Huerta-Cantillo J, Chavez-Duenas L, Zaidi M, Estrada-Garcia T, Navarro-Garcia F Med Microbiol Immunol. 2025; 214(1):7.

PMID: 39894890 PMC: 11788229. DOI: 10.1007/s00430-025-00816-4.

Intratumoral in Pancreatic Cancer: Current and Future Perspectives.

DAntonio D, Zenoniani A, Umme S, Piattelli A, Curia M Pathogens. 2025; 14(1).

PMID: 39860963 PMC: 11768203. DOI: 10.3390/pathogens14010002.

Beyond Tumor Borders: Intratumoral Microbiome Effects on Tumor Behavior and Therapeutic Responses.

Harmak Z, Kone A, Ghouzlani A, Ghazi B, Badou A Immune Netw. 2025; 24(6):e40.

PMID: 39801738 PMC: 11711125. DOI: 10.4110/in.2024.24.e40.

Genomic epidemiology and genetic characteristics of clinical species cocirculating in West Bengal, India, 2019, using whole genome analysis.

Morita D, Mukhopadhyay A, Chowdhury G, Maruyama F, Kanda M, Yamamoto Y Antimicrob Agents Chemother. 2024; 69(1):e0110824.

PMID: 39629976 PMC: 11784092. DOI: 10.1128/aac.01108-24.

References

Obert S, OConnor R, Schmid S, Hearing P . The adenovirus E4-6/7 protein transactivates the E2 promoter by inducing dimerization of a heteromeric E2F complex. Mol Cell Biol. 1994; 14(2):1333-46. PMC: 358488. DOI: 10.1128/mcb.14.2.1333-1346.1994. View

Cope L, Lumbley S, Latimer J, STEVENS M, Johnson L, Purven M . A diffusible cytotoxin of Haemophilus ducreyi. Proc Natl Acad Sci U S A. 1997; 94(8):4056-61. PMC: 20567. DOI: 10.1073/pnas.94.8.4056. View

Guzman L, Belin D, CARSON M, Beckwith J . Tight regulation, modulation, and high-level expression by vectors containing the arabinose PBAD promoter. J Bacteriol. 1995; 177(14):4121-30. PMC: 177145. DOI: 10.1128/jb.177.14.4121-4130.1995. View

Okuda J, Kurazono H, Takeda Y . Distribution of the cytolethal distending toxin A gene (cdtA) among species of Shigella and Vibrio, and cloning and sequencing of the cdt gene from Shigella dysenteriae. Microb Pathog. 1995; 18(3):167-72. DOI: 10.1016/s0882-4010(95)90022-5. View

Collazo C, Galan J . Requirement for exported proteins in secretion through the invasion-associated type III system of Salmonella typhimurium. Infect Immun. 1996; 64(9):3524-31. PMC: 174258. DOI: 10.1128/iai.64.9.3524-3531.1996. View

Hazes B . The (QxW)3 domain: a flexible lectin scaffold. Protein Sci. 1996; 5(8):1490-501. PMC: 2143495. DOI: 10.1002/pro.5560050805. View

Jones S, Worrall A, Connolly B . Site-directed mutagenesis of the catalytic residues of bovine pancreatic deoxyribonuclease I. J Mol Biol. 1996; 264(5):1154-63. DOI: 10.1006/jmbi.1996.0703. View

Wooldridge K, Ketley J . Campylobacter-host cell interactions. Trends Microbiol. 1997; 5(3):96-102. DOI: 10.1016/S0966-842X(97)01004-4. View

Purven M, Frisk A, Lonnroth I, Lagergard T . Purification and identification of Haemophilus ducreyi cytotoxin by use of a neutralizing monoclonal antibody. Infect Immun. 1997; 65(8):3496-9. PMC: 175498. DOI: 10.1128/iai.65.8.3496-3499.1997. View

10.

Comayras C, Tasca C, Peres S, Ducommun B, Oswald E, De Rycke J . Escherichia coli cytolethal distending toxin blocks the HeLa cell cycle at the G2/M transition by preventing cdc2 protein kinase dephosphorylation and activation. Infect Immun. 1997; 65(12):5088-95. PMC: 175733. DOI: 10.1128/iai.65.12.5088-5095.1997. View

11.

Whitehouse C, Balbo P, Pesci E, Cottle D, Mirabito P, Pickett C . Campylobacter jejuni cytolethal distending toxin causes a G2-phase cell cycle block. Infect Immun. 1998; 66(5):1934-40. PMC: 108146. DOI: 10.1128/IAI.66.5.1934-1940.1998. View

12.

Sugai M, Kawamoto T, Peres S, Ueno Y, Komatsuzawa H, Fujiwara T . The cell cycle-specific growth-inhibitory factor produced by Actinobacillus actinomycetemcomitans is a cytolethal distending toxin. Infect Immun. 1998; 66(10):5008-19. PMC: 108622. DOI: 10.1128/IAI.66.10.5008-5019.1998. View

13.

Cortes-Bratti X, Chaves-Olarte E, Lagergard T, Thelestam M . The cytolethal distending toxin from the chancroid bacterium Haemophilus ducreyi induces cell-cycle arrest in the G2 phase. J Clin Invest. 1999; 103(1):107-15. PMC: 407857. DOI: 10.1172/JCI3831. View

14.

Evans S, Shipstone E, Maughan W, Connolly B . Site-directed mutagenesis of phosphate-contacting amino acids of bovine pancreatic deoxyribonuclease I. Biochemistry. 1999; 38(13):3902-9. DOI: 10.1021/bi9824893. View

15.

Shenker B, McKay T, Datar S, Miller M, Chowhan R, Demuth D . Actinobacillus actinomycetemcomitans immunosuppressive protein is a member of the family of cytolethal distending toxins capable of causing a G2 arrest in human T cells. J Immunol. 1999; 162(8):4773-80. View

16.

Pickett C, Whitehouse C . The cytolethal distending toxin family. Trends Microbiol. 1999; 7(7):292-7. DOI: 10.1016/s0966-842x(99)01537-1. View

17.

Mead P, Slutsker L, Dietz V, McCaig L, Bresee J, Shapiro C . Food-related illness and death in the United States. Emerg Infect Dis. 1999; 5(5):607-25. PMC: 2627714. DOI: 10.3201/eid0505.990502. View

18.

Young V, Knox K, Schauer D . Cytolethal distending toxin sequence and activity in the enterohepatic pathogen Helicobacter hepaticus. Infect Immun. 1999; 68(1):184-91. PMC: 97119. DOI: 10.1128/IAI.68.1.184-191.2000. View

19.

Liu Q, Ribecco M, Pandey S, Walker P, Sikorska M . Apoptosis-related functional features of the DNaseI-like family of nucleases. Ann N Y Acad Sci. 2000; 887:60-76. DOI: 10.1111/j.1749-6632.1999.tb07922.x. View

20.

Parkhill J, Wren B, Mungall K, Ketley J, Churcher C, Basham D . The genome sequence of the food-borne pathogen Campylobacter jejuni reveals hypervariable sequences. Nature. 2000; 403(6770):665-8. DOI: 10.1038/35001088. View