Cytolethal Distending Toxin Family Members Are Differentially Affected by Alterations in Host Glycans and Membrane Cholesterol

Overview

Journal J Biol Chem

Specialty Biochemistry

Date 2010 Apr 14

PMID 20385557

Citations 41

Authors

Aria Eshraghi

Francisco J Maldonado-Arocho

Amandeep Gargi

Marissa M Cardwell

Michael G Prouty

Steven R Blanke

Kenneth A Bradley

Affiliations

Soon will be listed here.

Abstract

Cytolethal distending toxins (CDTs) are tripartite protein exotoxins produced by a diverse group of pathogenic Gram-negative bacteria. Based on their ability to induce DNA damage, cell cycle arrest, and apoptosis of cultured cells, CDTs are proposed to enhance virulence by blocking cellular division and/or directly killing epithelial and immune cells. Despite the widespread distribution of CDTs among several important human pathogens, our understanding of how these toxins interact with host cells is limited. Here we demonstrate that CDTs from Haemophilus ducreyi, Aggregatibacter actinomycetemcomitans, Escherichia coli, and Campylobacter jejuni differ in their abilities to intoxicate host cells with defined defects in host factors previously implicated in CDT binding, including glycoproteins, and glycosphingolipids. The absence of cell surface sialic acid sensitized cells to intoxication by three of the four CDTs tested. Surprisingly, fucosylated N-linked glycans and glycolipids, previously implicated in CDT-host interactions, were not required for intoxication by any of the CDTs tested. Finally, altering host-cellular cholesterol, also previously implicated in CDT binding, affected intoxication by only a subset of CDTs tested. The findings presented here provide insight into the molecular and cellular basis of CDT-host interactions.

Citing Articles

Cellugyrin (synaptogyrin-2) dependent pathways are used by bacterial cytolethal distending toxin and SARS-CoV-2 virus to gain cell entry.

Boesze-Battaglia K, Cohen G, Bates P, Walker L, Zekavat A, Shenker B Front Cell Infect Microbiol. 2024; 14:1334224.

PMID: 38698905 PMC: 11063343. DOI: 10.3389/fcimb.2024.1334224.

extracellular vesicles harboring cytolethal distending toxin bind host cell glycans and induce cell cycle arrest in host cells.

Le L, Elgamoudi B, Colon N, Cramond A, Poly F, Ying L Microbiol Spectr. 2024; 12(3):e0323223.

PMID: 38319111 PMC: 10913475. DOI: 10.1128/spectrum.03232-23.

Revisiting bacterial cytolethal distending toxin structure and function.

Chen H, Ang C, Crowder M, Brieher W, Blanke S Front Cell Infect Microbiol. 2023; 13:1289359.

PMID: 38035327 PMC: 10682658. DOI: 10.3389/fcimb.2023.1289359.

Presence of Functionally Active Cytolethal Distending Toxin Genes on a Conjugative Plasmid in a Clinical Isolate of Providencia rustigianii.

Hassan J, Awasthi S, Hatanaka N, Hoang P, Nagita A, Hinenoya A Infect Immun. 2023; 91(6):e0012122.

PMID: 37158737 PMC: 10269090. DOI: 10.1128/iai.00121-22.

Targeting the Inside of Cells with Biologicals: Toxin Routes in a Therapeutic Context.

Ruschig M, Marschall A BioDrugs. 2023; 37(2):181-203.

PMID: 36729328 PMC: 9893211. DOI: 10.1007/s40259-023-00580-y.

References

Nesic D, Hsu Y, Stebbins C . Assembly and function of a bacterial genotoxin. Nature. 2004; 429(6990):429-33. DOI: 10.1038/nature02532. 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

Patnaik S, Stanley P . Lectin-resistant CHO glycosylation mutants. Methods Enzymol. 2006; 416:159-82. DOI: 10.1016/S0076-6879(06)16011-5. View

Nesic D, Stebbins C . Mechanisms of assembly and cellular interactions for the bacterial genotoxin CDT. PLoS Pathog. 2005; 1(3):e28. PMC: 1287909. DOI: 10.1371/journal.ppat.0010028. View

Smith J, Bayles D . The contribution of cytolethal distending toxin to bacterial pathogenesis. Crit Rev Microbiol. 2006; 32(4):227-48. DOI: 10.1080/10408410601023557. View

Nougayrede J, Taieb F, De Rycke J, Oswald E . Cyclomodulins: bacterial effectors that modulate the eukaryotic cell cycle. Trends Microbiol. 2005; 13(3):103-10. DOI: 10.1016/j.tim.2005.01.002. View

Lee R, Hassane D, Cottle D, Pickett C . Interactions of Campylobacter jejuni cytolethal distending toxin subunits CdtA and CdtC with HeLa cells. Infect Immun. 2003; 71(9):4883-90. PMC: 187314. DOI: 10.1128/IAI.71.9.4883-4890.2003. View

Johnson W, Lior H . A new heat-labile cytolethal distending toxin (CLDT) produced by Campylobacter spp. Microb Pathog. 1988; 4(2):115-26. DOI: 10.1016/0882-4010(88)90053-8. View

Guerra L, Teter K, Lilley B, Stenerlow B, Holmes R, Ploegh H . Cellular internalization of cytolethal distending toxin: a new end to a known pathway. Cell Microbiol. 2005; 7(7):921-34. DOI: 10.1111/j.1462-5822.2005.00520.x. View

10.

Larsen R, Ernst L, Nair R, Lowe J . Molecular cloning, sequence, and expression of a human GDP-L-fucose:beta-D-galactoside 2-alpha-L-fucosyltransferase cDNA that can form the H blood group antigen. Proc Natl Acad Sci U S A. 1990; 87(17):6674-8. PMC: 54599. DOI: 10.1073/pnas.87.17.6674. View

11.

Carette J, Guimaraes C, Varadarajan M, Park A, Wuethrich I, Godarova A . Haploid genetic screens in human cells identify host factors used by pathogens. Science. 2009; 326(5957):1231-5. DOI: 10.1126/science.1178955. View

12.

Hong Y, Sundaram S, Shin D, Stanley P . The Lec23 Chinese hamster ovary mutant is a sensitive host for detecting mutations in alpha-glucosidase I that give rise to congenital disorder of glycosylation IIb (CDG IIb). J Biol Chem. 2004; 279(48):49894-901. DOI: 10.1074/jbc.M410121200. View

13.

Bradley K, Mogridge J, Jonah G, Rainey A, Batty S, Young J . Binding of anthrax toxin to its receptor is similar to alpha integrin-ligand interactions. J Biol Chem. 2003; 278(49):49342-7. DOI: 10.1074/jbc.M307900200. View

14.

Lara-Tejero M, Galan J . A bacterial toxin that controls cell cycle progression as a deoxyribonuclease I-like protein. Science. 2000; 290(5490):354-7. DOI: 10.1126/science.290.5490.354. View

15.

Shenker B, Hoffmaster R, Zekavat A, Yamaguchi N, Lally E, Demuth D . Induction of apoptosis in human T cells by Actinobacillus actinomycetemcomitans cytolethal distending toxin is a consequence of G2 arrest of the cell cycle. J Immunol. 2001; 167(1):435-41. DOI: 10.4049/jimmunol.167.1.435. View

16.

Mathieu S, Prorok M, Benoliel A, Uch R, Langlet C, Bongrand P . Transgene expression of alpha(1,2)-fucosyltransferase-I (FUT1) in tumor cells selectively inhibits sialyl-Lewis x expression and binding to E-selectin without affecting synthesis of sialyl-Lewis a or binding to P-selectin. Am J Pathol. 2004; 164(2):371-83. PMC: 1602278. DOI: 10.1016/s0002-9440(10)63127-6. View

17.

Lidholt K, Weinke J, Kiser C, Lugemwa F, Bame K, Cheifetz S . A single mutation affects both N-acetylglucosaminyltransferase and glucuronosyltransferase activities in a Chinese hamster ovary cell mutant defective in heparan sulfate biosynthesis. Proc Natl Acad Sci U S A. 1992; 89(6):2267-71. PMC: 48638. DOI: 10.1073/pnas.89.6.2267. View

18.

Stanley P . Chinese hamster ovary cell mutants with multiple glycosylation defects for production of glycoproteins with minimal carbohydrate heterogeneity. Mol Cell Biol. 1989; 9(2):377-83. PMC: 362611. DOI: 10.1128/mcb.9.2.377-383.1989. View

19.

Oelmann S, Stanley P, Gerardy-Schahn R . Point mutations identified in Lec8 Chinese hamster ovary glycosylation mutants that inactivate both the UDP-galactose and CMP-sialic acid transporters. J Biol Chem. 2001; 276(28):26291-300. DOI: 10.1074/jbc.M011124200. View

20.

Hanada K, Hara T, Fukasawa M, Yamaji A, Umeda M, Nishijima M . Mammalian cell mutants resistant to a sphingomyelin-directed cytolysin. Genetic and biochemical evidence for complex formation of the LCB1 protein with the LCB2 protein for serine palmitoyltransferase. J Biol Chem. 1998; 273(50):33787-94. DOI: 10.1074/jbc.273.50.33787. View