Cytolethal distending toxin: from genotoxin to a potential biomarker and anti-tumor target.

Abstract

Cytolethal Distending Toxin (CDT) belongs to the AB toxin family and is produced by a plethora of Gram-negative bacteria. Eight human-affecting enteropathogens harbor CDT that causes irritable bowel syndrome (IBS), dysentery, chancroid, and periodontitis worldwide. They have a novel molecular mode of action as they interfere in the eukaryotic cell-cycle progression leading to G2/M arrest and apoptosis. CDT, the first bacterial genotoxin described, is encoded in a single operon possessing three proteins, CdtA, CdtB, and CdtC. CdtA and CdtC are needed for the binding of the CDT toxin complex to the cholesterol-rich lipid domains of the host cell while the CdtB is the active moiety. Sequence and 3D structural-based analysis of CdtB showed similarities with nucleases and phosphatases, it was hypothesized that CdtB exercises a biochemical function identical to both these enzymes. CDT is secreted through the outer membrane vesicles from the producing bacteria. It is internalized in the target cells via clathrin-dependent endocytosis and translocated to the host cell nucleus through the Golgi complex and ER. This study discusses the virulence role of CDT, causing pathogenicity by acting as a tri-perditious complex in the CDT-producing species with an emphasis on its potential role as a biomarker and an anti-tumor agent.