Abstract
The cytolethal distending toxin (Cdt) is a heterotrimeric holotoxin produced by a diverse group of Gram-negative pathogenic bacteria. The Cdts expressed by the members of this group comprise a subclass of the AB toxin superfamily. Some AB toxins have hijacked the retrograde transport pathway, carried out by the Golgi apparatus and endoplasmic reticulum (ER), to translocate to cytosolic targets. Those toxins have been used as tools to decipher the roles of the Golgi and ER in intracellular transport and to develop medically useful delivery reagents. In comparison to the other AB toxins, the Cdt exhibits unique properties, such as translocation to the nucleus, that present specific challenges in understanding the precise molecular details of the trafficking pathway in mammalian cells. The purpose of this review is to present current information about the mechanisms of uptake and translocation of the Cdt in relation to standard concepts of endocytosis and retrograde transport. Studies of the Cdt intoxication process to date have led to the discovery of new translocation pathways and components and most likely will continue to reveal unknown features about the mechanisms by which bacterial proteins target the mammalian cell nucleus. Insight gained from these studies has the potential to contribute to the development of novel therapeutic strategies.
Highlights
The cytolethal distending toxin (Cdt) is a subclass of the AB toxin superfamily
EGA failed to alter the effect of EcCdt on cell viability. These findings suggest that the HdCdt is transported by the late endocytic pathway and the EcCdt, like some of the other AB toxins, may be translocated by early endosomes
Retrograde transport of toxins via the Golgi apparatus and endoplasmic reticulum (ER) requires a complex cascade of supporting protein chaperones, protein complexes, small GTPases and unidentified components
Summary
The cytolethal distending toxin (Cdt) is a subclass of the AB toxin superfamily. Typical members of this subclass are produced by Gram-negative bacteria and those that are expressed from a complete cdt operon have an AB2 subunit configuration. The structural and biological complexity of the Cdt, compared to that of other AB toxins, has made it a challenge to elucidate the mechanistic details of transport and trafficking. This review strives to present current information and hypotheses about the synthesis of the Cdt and mechanism(s) of infection of susceptible target cells. AB toxins that travel from the cell membrane to the ER and the nucleus provide novel model systems that can be used to (i) study retrograde transport pathways,. (ii) elucidate the regulation of protein trafficking and (iii) design strategies for the precise localized delivery of therapeutic agents
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