The biology of the cytolethal distending toxins

Abstract

The cytolethal distending toxins (CDTs), produced by a variety of Gram-negative pathogenic bacteria, are the first bacterial genotoxins described, since they cause DNA damage in the target cells. CDT is an A-B(2) toxin, where the CdtA and CdtC subunits are required to mediate the binding on the surface of the target cells, allowing internalization of the active CdtB subunit, which is functionally homologous to the mammalian deoxyribonuclease I. The nature of the surface receptor is still poorly characterized, however binding of CDT requires intact lipid rafts, and its internalization occurs via dynamin-dependent endocytosis. The toxin is retrograde transported through the Golgi complex and the endoplasmic reticulum, and subsequently translocated into the nuclear compartment, where it exerts the toxic activity. Cellular intoxication induces DNA damage and activation of the DNA damage responses, which results in arrest of the target cells in the G1 and/or G2 phases of the cell cycle and activation of DNA repair mechanisms. Cells that fail to repair the damage will senesce or undergo apoptosis. This review will focus on the well-characterized aspects of the CDT biology and discuss the questions that still remain unanswered.

Keywords: DNA damage; DNA damage response; bacterial genotoxin; chancroid; colitis/hepatitis; cytolethal distending toxin; periodontitis; survival signals; toxin internalization; virulence factor.

Figure 1

Cytolethal distending toxin (CDT) internalization pathway. Binding of CDT is dependent on the presence of intact lipid rafts, and the toxin is internalized via dynamin-dependent endocytosis into early and late endosomes. The CdtB subunit further transits to the Golgi complex, and is then retrogradely transported to the endoplasmic reticulum (ER). Translocation from the ER does not require the ER-associated degradation (ERAD) pathway, and protein unfolding.

Figure 2

CDT-induced cellular responses. The protein kinase ATM is activated upon CDT-induced DNA damage. c-MYC is required for proper activation of the ATM-dependent DNA damage response, which in turn recruits phosphorylated histone H2AX and the DNA repair proteins, such as the MRN complex, at the sites of DNA strand break. As consequence of the DNA damage checkpoint responses, cells are arrested in the different phases of the cell cycle, and in case of failure to properly repair the DNA damage, they senesce or die by apoptosis. CDT-induced DNA damage promotes dephosphorylation of Net1, and consequent activation of RhoA, which regulates two distinct pathways: (1) induction of actin stress fibers, which requires the RhoA kinases ROCKI and ROCKII; (2) activation of p38 MAPK, associated with a delayed cell death. The characteristic distension observed in epithelial cells is dependent on activation of the PI3-kinase (PI3K) and its downstream effector mTOR.

Figure 3

Schematic representation of the possible role of CDT in the pathogenesis of three bacterial diseases: chancroid (H. ducreyi), periodontitis (A. actinomicetemcomitans), and chronic colitis or hepatitis (Campylobacter and Helicobacter sp).