A Journey of Cytolethal Distending Toxins through Cell Membranes

Abstract

The multifunctional role of lipids as structural components of membranes, signaling molecules, and metabolic substrates makes them an ideal partner for pathogens to hijack host cell processes for their own survival. The properties and composition of unique membrane micro-domains such as membrane rafts make these regions a natural target for pathogens as it affords them an opportunity to hijack cell signaling and intracellular trafficking pathways. Cytolethal distending toxins (Cdts), members of the AB2 family of toxins are comprised of three subunits, the active, CdtB unit, and the binding, CdtA-CdtC unit. Cdts are cyclomodulins leading to cell cycle arrest and apoptosis in a wide variety of cell types. Cdts from several species share a requirement for membrane rafts, and often cholesterol specifically for cell binding and CdtB mediated cytotoxicity. In this review we focus on how host-cell membrane bilayer organization contributes to the cell surface association, internalization, and action of bacteria derived cytolethal distending toxins (Cdts), with an emphasis on Aggregatibacter actinomycetemcomitans Cdt.

Keywords: CRAC site; PI3K pathway inhibitors; cholesterol; cytolethal distending toxin (CDT); phosphatases.

Figure 1

Schematic representation of Cdt-cell surface association, internalization, and intracellular activity. Details of these processes are described in the text. Briefly, Cdt holotoxin binds cholesterol rich membrane rafts. Several different pathways have been implicated for the internalization of the CdtB and CdtC subunits; it is possible that the operative pathway may be Cdt sub type specific or host cell specific. Once internalized CdtB traffics to the Golgi, ER, and ultimately to the nucleus and/or cytoplasm. Internalized CdtB exerts toxicity either through its ability to act as a DNase and/or lipid phosphatase converting PI3,4,5,P3 to PI, 4,5P2 leading to PI-3K signaling blockade. Phosphoinositide pools, particularly PIP3, are likely plasma membrane associated, perhaps in the context of membrane rafts or a component of the endosomal substrate pool as indicated by the light blue circles on endosomes which represent PI3,4,5P3. Orange-yellow circles represent cholesterol.