Molecular Mechanisms and Potential Clinical Applications of Campylobacter jejuni Cytolethal Distending Toxin.

Cheng-Kuo Lai,Hwai-Jeng Lin,Min-Chuan Kao,Yu-Hsin Lin,Yu-An Chen,Li-Chiung Lin,Mei-Zi Huang,U-Ging Lo,Ho Lin,Chih-Jung Chen,Chuan Chiang-Ni,Chun-Jung Lin,Jer-Tsong Hsieh,Chih-Ho Lai

doi:10.3389/fcimb.2016.00009

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.

Highlights

Campylobacter jejuni, a gram-negative bacterium, is one of the most common causative agents of food-borne infectious illnesses in humans (Butzler and Skirrow, 1979; Mead et al, 1999)
An analysis of Aa-CDT revealed that CdtA and CdtC were both bound to the cell membrane and associated with lipid rafts (Boesze-Battaglia et al, 2006), which contain abundant cholesterol, phospholipids, and sphingolipids (Brown and London, 1998)
A study of C. jejuni revealed that treatment of cells with MβCD partially inhibited OMVinduced inflammation, indicating that membrane rafts provided a certain role for C. jejuni outer-membrane vesicles (OMVs)-mediated signal transduction (Elmi et al, 2012). These findings suggest that OMV interactions with lipid rafts may promote the delivery of Cj-CDT to target cells and enhance the efficiency of cell intoxication

Summary

Introduction

Campylobacter jejuni, a gram-negative bacterium, is one of the most common causative agents of food-borne infectious illnesses in humans (Butzler and Skirrow, 1979; Mead et al, 1999). Cj-CdtA and Cj-CdtC are required for assembling a tripartite complex with Cj-CdtB for holotoxin activity (Lara-Tejero and Galan, 2001) and binding to the plasma membrane of cells (Bag et al, 1993). An analysis of Aa-CDT revealed that CdtA and CdtC were both bound to the cell membrane and associated with lipid rafts (Boesze-Battaglia et al, 2006), which contain abundant cholesterol, phospholipids, and sphingolipids (Brown and London, 1998).

Results

Conclusion