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. 2021 Jan 6;13(1):36. doi: 10.3390/toxins13010036

Table 1.

Summary of the internalization mechanism steps of botulinum toxin type A, anthrax toxin, and cholera toxin as well as their use in therapeutic applications.

Botulinum Toxin Type A Anthrax Toxin Cholera Toxin
Bacterium Clostridium bacteria family Bacillus anthracis Vibrio cholerae
A subunit BoNT light chain (LC) Lethal factor (LF) Cholera toxin A1 and A2 (CTA1 and CTA2)
B subunit BoNT heavy chain (HC) Protective Antigen (PA) Cholera toxin B (CTB)
Receptors Polysialogangliosides and SV2 [10,11] CMG2 and TEM8 [12,13] GM1 [14]
Oligomerization None A3B7 or A4B8 [15,16] AB5 [5,17,18]
Cellular compartments From synaptic membrane to synaptic vesicles [19,20] From plasma membrane to early endosomes and late endosomes [21] From plasma membrane to early endosomes and retro-translocation to the Golgi and ER [22,23]
Membrane translocation mechanism HC translocates LC through the membrane [24] PA pore translocating LF across the membrane [25,26] Uses the ERAD-associated translocation mechanism [27]
Cytosolic target SNAP-25 (of the SNARE complex) [28] LF cleaves MAPKK family members [29] Activates Gαs [27]
Therapeutic applications

  • Intrinsic properties

  • Use in the treatment of dystonic and spastic disorders [30]

  • Use in the treatment of autonomic disorders [31]

  • Use in pain therapy [7]

  • Treatment of cancer relying on the MAPKK-associated pathways [32,33]

  • Use as adjuvant in mucosal vaccines [34,35]

  • Use of an inactive CT to temporarily occupy the ERAD-associated translocation machinery in the treatments of genetic protein misfolding diseases [36]

  • Use of CTB retro-translocation property to image neuronal cells [37]

  • A subunit modularity

  • Cytosolic transport of LCE using LCA-HCA as a delivery system [38]

  • Delivery of non-native protein or small molecule cargos using PA-LFN delivery system [39,40,41,42,43,44,45]

  • Vaccines development consisting of antigens fused with CTA2 and delivered using CTB [46,47,48]

  • B subunit modularity

  • Use of other botulinum toxin HC (i.e HCB) to increase LCA uptake [49]

  • Targeting of non-native receptors to inhibit protein secretion [50,51]

  • Cell-specific delivery of cargos using non-native protease-specific PA [52,53,54]

  • Targeting to non-native receptors using Affibodies, DARPins or receptors ligand for the cytosolic delivery of non-native cargos [55,56,57,58]

  • Conjugation of self and non-self antigens to CTB to increase antigen uptake in the development of therapies against pathogens, autoimmune and inflammatory diseases [18,59]

  • CTB-KDEL fusion protein to induce ER retention and UPR-mediated wound healing response in colon [60]

  • Use of CTB ability to cross the blood-brain barrier and target neuronal cells to deliver drugs [61]