Figure 1.

Comparative mode of action of AB-type toxins. (A) AB toxins. The B subunit of AB toxins binds to targeted host cell receptors to initiate receptor-mediated endocytosis. The endosome then becomes acidified and the A and B subunits disassociate. In the case of the diphtheria toxin and exotoxin A of Pseudomonas aeruginosa, the A subunit targets elongation factor 2 to inhibit host cell protein synthesis and cause apoptosis (a). The A subunit (light chain) of botulinum neurotoxins cleaves specific proteins in soluble N-ethylmaleimide–sensitive factor-activating protein receptor (SNARE) complexes, blocking the release of acetylcholine from presynaptic nerve endings (b). This also inhibits neurotransmitter-containing vesicles from fusing to presynaptic membranes, resulting in flaccid paralysis, muscle weakness, blurred vision, and slurred speech; (B) AB₂ toxins. The B subunit of AB₂ toxins binds to specific host cell ganglioside receptors (a) or to membrane lipid raft microdomains (b) to allow the A subunit to become endocytosed. The A subunit then localizes to the nucleus via the Golgi apparatus and endoplasmic reticulum (ER). In the case of the cytolethal distending toxin (CDT), the A subunit utilizes its type I DNase activity to create double-stranded breaks in host cell chromosomal DNA, activating the DNA damage response and irreversibly arresting the cell in the G₂/M phase of the cell cycle to cause apoptosis; (C) AB₅ toxins. The holotoxins bind to specific host cell receptors to become endocytosed and undergo retrograde trafficking via early endosomes to the ER through the Golgi apparatus. At the ER, the holotoxin is cleaved, allowing the A subunit to elicit its cytotoxic effects. The A subunit of AB₅ toxins can target G proteins and adenylyl cyclase, which will increase intracellular cAMP levels and lead to fluid secretion and diarrhea (a). The A subunit also targets ER chaperone proteins, leading to an accumulation of unfolded proteins in the ER to activate the ER stress response and cause apoptosis (b). Lastly, A subunits target residues in 28S rRNA to inhibit protein synthesis, initiate a ribotoxic stress response, and cause apoptosis of host cells (c). Created in BioRender.com (Aoki, S., K. Shteyn, and R. Marien, BioRender. Toronto, ON, Canada, Accessed on 4 August 2021).