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-B2 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.

Listeria monocytogenesinduces host DNA damage and delays the host cell cycle to promote infection

“…5,42 Lm was never associated with enhanced risk in cancer development, and persistent Lm infections are yet poorly supported. However, wild-type Lm and highly attenuated mutants were found to persist in small foci in the mouse bone marrow.…”

When our genome is targeted by pathogenic bacteria

“…Many gram-negative pathogenic bacteria such as Haemophilus ducreyi, Campylobacter jejuni, E. coli, Shigella dysenteriae, Salmonella typhi, and Helicobacter hepaticus, produce this toxin comprising 3 subunits, CdtA, CdtB and CdtC. While CdtA and CdtC are crucial for holotoxin internalization, CdtB harbors structural and functional similarities to mammalian DNase I [34,36]. CDT is secreted from bacteria prior to binding to the cell surface where this enzyme is internalized through endocytosis via several trafficking pathways and subsequently relocalized to the eukaryotic nucleus [36].…”

“…While CdtA and CdtC are crucial for holotoxin internalization, CdtB harbors structural and functional similarities to mammalian DNase I [34,36]. CDT is secreted from bacteria prior to binding to the cell surface where this enzyme is internalized through endocytosis via several trafficking pathways and subsequently relocalized to the eukaryotic nucleus [36]. The microinjection of purified CDT in the cell nucleus triggers chromatin fragmentation [37].…”

“…The microinjection of purified CDT in the cell nucleus triggers chromatin fragmentation [37]. In the presence of high doses of CDT, cells rapidly accumulate DSBs [36][37][38] with the concomitant formation of nuclear IRIF-like foci containing γH2AX and 53BP1 [37,39,40] and the strong activation of ATM-Chk2 and ATR-Chk1 signaling axes [40]. Depending on the type of cells challenged with CDT, the activation of the ATM-Chk2-p53 pathway results in G1 and /or G2 arrest, followed by cell death [41].…”

“…Depending on the type of cells challenged with CDT, the activation of the ATM-Chk2-p53 pathway results in G1 and /or G2 arrest, followed by cell death [41]. Epithelial or mesenchymal cells intoxicated with CDT die after several days, whereas more fragile lymphocytes die more rapidly through apoptosis [36]. In yeast, homologous recombination is the predominant DNA repair mechanism for protection against CDT-induced lesions [42], whereas in human cells, both HR and NHEJ repair pathways protect against CDT-induced DSBs [40].…”