title: Cholesterol depletion reduces entry of Campylobacter jejuni cytolethal distending toxin and attenuates intoxication of host cells.
abstract: Campylobacter jejuni is a common cause of pediatric diarrhea worldwide. Cytolethal distending toxin, produced by Campylobacter jejuni, is a putative virulence factor that induces cell cycle arrest and apoptosis in eukaryotic cells. Cellular cholesterol, a major component of lipid rafts, has a pivotal role in regulating signaling transduction and protein trafficking as well as pathogen internalization. In this study, we demonstrated that cell intoxication by Campylobacter jejuni cytolethal distending toxin is through the association of cytolethal distending toxin subunits and membrane cholesterol-rich microdomains. Cytolethal distending toxin subunits cofractionated with detergent-resistant membranes, while the distribution reduced upon the depletion of cholesterol, suggesting that cytolethal distending toxin subunits are associated with lipid rafts. The disruption of cholesterol using methyl-β-cyclodextrin not only reduced the binding activity of cytolethal distending toxin subunits on the cell membrane but also impaired their delivery and attenuated toxin-induced cell cycle arrest. Accordingly, cell intoxication by cytolethal distending toxin was restored by cholesterol replenishment. These findings suggest that membrane cholesterol plays a critical role in the Campylobacter jejuni cytolethal distending toxin-induced pathogenesis of host cells.
authors: School of Medicine and Graduate Institute of Basic Medical Science, China Medical University, No. 91 Hsueh-Shih Road, Taichung, 40402 Taiwan.
authors: Chia-Der
authors: CD
authors: Lin
authors: Cheng-Kuo
authors: CK
authors: Lai
authors: Yu-Hsin
authors: YH
authors: Lin
authors: Jer-Tsong
authors: JT
authors: Hsieh
authors: Yu-Ting
authors: YT
authors: Sing
authors: Yun-Chieh
authors: YC
authors: Chang
authors: Kai-Chuan
authors: KC
authors: Chen
authors: Wen-Ching
authors: WC
authors: Wang
authors: Hong-Lin
authors: HL
authors: Su
authors: Chih-Ho
authors: CH
authors: Lai
mesh_terms: D000818:Animals; D001427:Bacterial Toxins / Q000235:genetics / Q000378:metabolism*; D016466:CHO Cells; D016123:Campylobacter jejuni / Q000378:metabolism / Q000472:pathogenicity*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism* / Q000494:pharmacology; D006224:Cricetinae; D003412:Cricetulus; D005434:Flow Cytometry; D006801:Humans; D021962:Membrane Microdomains / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D037521:Virulence Factors / Q000378:metabolism; D047392:beta-Cyclodextrins / Q000494:pharmacology
chemical_list: D001427:Bacterial Toxins; D037521:Virulence Factors; D047392:beta-Cyclodextrins; C067044:cytolethal distending toxin; C108732:methyl-beta-cyclodextrin; D002784:Cholesterol