title: Molecular Mechanisms and Potential Clinical Applications of Campylobacter jejuni Cytolethal Distending Toxin.
abstract: Cytolethal distending toxin (CDT), a genotoxin produced by Campylobacter jejuni, is composed of three subunits: CdtA, CdtB, and CdtC. CdtB is a DNase that causes DNA double-strand breaks (DSB) in the nucleus resulting in cell cycle arrest at the G2/M stage and apoptosis. CdtA and CdtC bind to cholesterol-rich microdomains on the cytoplasmic membrane, a process required for the delivery of CdtB to cells. Although a unique motif associated with cholesterol-binding activity has been identified in other pathogens, the mechanism underlying the interaction between the CdtA and CdtC subunits and membrane cholesterol remains unclear. Also, the processes of cell uptake and delivery of CdtB in host cells and the translocation of CdtB into the nucleus are only partially understood. In this review, we focus on the underlying relationship among CDT, membrane cholesterol, and the intracellular trafficking pathway as a unique mechanism for C. jejuni-induced pathogenesis. Moreover, we discuss the clinical aspects of a possible therapeutic application of CDT in cancer therapy. Understanding the molecular mechanism of CDT-host interactions may provide insights into novel strategies to control C. jejuni infection and the development of potential clinical applications of CDT.
authors.affiliation: Department of Microbiology and Immunology, Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung UniversityTaoyuan, Taiwan; Department of Urology, University of Texas Southwestern Medical CenterDallas, TX, USA.
authors.forename: Cheng-Kuo
authors.initials: CK
authors.lastname: Lai
authors.affiliation: School of Medicine, Graduate Institute of Basic Medical Science, China Medical University Taichung, Taiwan.
authors.forename: Yu-An
authors.initials: YA
authors.lastname: Chen
authors.affiliation: Department of Urology, University of Texas Southwestern Medical CenterDallas, TX, USA; School of Medicine, Graduate Institute of Basic Medical Science, China Medical UniversityTaichung, Taiwan.
authors.forename: Chun-Jung
authors.initials: CJ
authors.lastname: Lin
authors.affiliation: Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical UniversityNew Taipei, Taiwan; Division of Gastroenterology and Hepatology, Department of Internal Medicine, Shuang-Ho HospitalNew Taipei, Taiwan.
authors.forename: Hwai-Jeng
authors.initials: HJ
authors.lastname: Lin
authors.affiliation: Department of Microbiology and Immunology, Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University Taoyuan, Taiwan.
authors.forename: Min-Chuan
authors.initials: MC
authors.lastname: Kao
authors.affiliation: Department of Microbiology and Immunology, Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung UniversityTaoyuan, Taiwan; School of Medicine, Graduate Institute of Basic Medical Science, China Medical UniversityTaichung, Taiwan.
authors.forename: Mei-Zi
authors.initials: MZ
authors.lastname: Huang
authors.affiliation: Department of Urology, University of Texas Southwestern Medical CenterDallas, TX, USA; Department of Biological Science and Technology, China Medical UniversityTaichung, Taiwan.
authors.forename: Yu-Hsin
authors.initials: YH
authors.lastname: Lin
authors.affiliation: Department of Microbiology and Immunology, Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University Taoyuan, Taiwan.
authors.forename: Chuan
authors.initials: C
authors.lastname: Chiang-Ni
authors.affiliation: Department of Pediatrics, Molecular Infectious Disease Research Center, Chang Gung Children's Hospital and Chang Gung Memorial Hospital Taoyuan, Taiwan.
authors.forename: Chih-Jung
authors.initials: CJ
authors.lastname: Chen
authors.affiliation: Department of Urology, University of Texas Southwestern Medical Center Dallas, TX, USA.
authors.forename: U-Ging
authors.initials: UG
authors.lastname: Lo
authors.affiliation: Department of Urology, University of Texas Southwestern Medical CenterDallas, TX, USA; Department of Life Sciences, National Chung Hsing UniversityTaichung, Taiwan.
authors.forename: Li-Chiung
authors.initials: LC
authors.lastname: Lin
authors.affiliation: Department of Life Sciences, National Chung Hsing University Taichung, Taiwan.
authors.forename: Ho
authors.initials: H
authors.lastname: Lin
authors.affiliation: Department of Urology, University of Texas Southwestern Medical CenterDallas, TX, USA; Graduate Institute of Cancer Biology, China Medical UniversityTaichung, Taiwan.
authors.forename: Jer-Tsong
authors.initials: JT
authors.lastname: Hsieh
authors.affiliation: Department of Microbiology and Immunology, Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung UniversityTaoyuan, Taiwan; School of Medicine, Graduate Institute of Basic Medical Science, China Medical UniversityTaichung, Taiwan; Department of Pediatrics, Molecular Infectious Disease Research Center, Chang Gung Children's Hospital and Chang Gung Memorial HospitalTaoyuan, Taiwan; Department of Nursing, Asia UniversityTaichung, Taiwan.
authors.forename: Chih-Ho
authors.initials: CH
authors.lastname: Lai
mesh_terms: D021581:Active Transport, Cell Nucleus; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D001427:Bacterial Toxins / Q000302:isolation & purification / Q000627:therapeutic use*; D016123:Campylobacter jejuni / Q000472:pathogenicity*; D002784:Cholesterol / Q000378:metabolism; D053903:DNA Breaks, Double-Stranded / Q000187:drug effects; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D006801:Humans; D021962:Membrane Microdomains / Q000378:metabolism*; D009369:Neoplasms / Q000188:drug therapy*
chemical_list: D000970:Antineoplastic Agents; D001427:Bacterial Toxins; C067044:cytolethal distending toxin; D002784:Cholesterol
keywords: Campylobacter jejuni; cholesterol; cytolethal distending toxin; enzymatic activity; trafficking