Cell entry strategy of clostridial neurotoxins

Abstract

vesicle protein 2; Syt, synaptotagmin; TeNT, tetanus neurotoxin. AbstractTetanus neurotoxin and botulinum neurotoxins are the causative agents of tetanus and botulism. They block the release of neurotransmitters from synaptic vesicles in susceptible animals and man and act in nanogram quantities because of their ability to specifically attack motoneurons. They developed an ingenious strategy to enter neurons. This involves a concentration step via complex polysialo gangliosides at the plasma membrane and the uptake and ride in recycling synaptic vesicles initiated by binding to a specific protein receptor. Finally, the neurotoxins shut down the synaptic vesicle cycle, which they had misused before to enter their target cells, via specific cleavage of protein core components of the cellular membrane fusion machinery. The uptake of four out of seven known botulinum neurotoxins into synaptic vesicles has been demonstrated to rely on binding to intravesicular segments of the synaptic vesicle proteins synaptotagmin or synaptic vesicle protein 2. This review summarizes the present knowledge about the cell receptor molecules and the mode of toxin-receptor interaction that enables the toxins' sophisticated access to their site of action.

Innocuous full-length botulinum neurotoxin targets and promotes the expression of lentiviral vectors in central and autonomic neurons

“…20,21 The suitability of BoNTs as vehicles for neuronal gene targeting and biomolecule delivery is further augmented by the existence of multiple serotypes (A-G), which have different ecto-acceptors for entry into various neuronal populations. 22,23 The pronounced specificity of BoNT/B for motor nerve endings and peripheral autonomic neurons renders it highly attractive as a potential targeting moiety. Notably, it has the advantages of using as a neuronal acceptor one of the most abundant synaptic vesicle proteins, synaptotagmin II (syt-II), which becomes exposed on nerve terminals upon exocytotic neurotransmitter release.…”

The potential of toxin-based drug delivery systems for enhanced nucleic acid therapeutic delivery

“…The toxin is synthesised as a 150 KDa molecule, which like RT is subject to proteolytic cleavage to produce a 100 KDa heavy chain and a 50 KDa light chain, responsible for proteolytic activity. After receptor binding, a membrane translocation event from the endosome to the cytosol occurs which, similar to DT, requires the multimerisation and membrane insertion of the heavy chain, followed by the unfolding and translocation of the light chain [81]. C. botulinum toxin serotypes A and B are used clinically, with botulinum toxin A being marketed as 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 [83].…”

“…Clostridium tetani toxin (TeNT) and C. botulinum toxin (BoNT) are responsible for tetanus and botulism (respectively) [81]. BoNT has seven distinct serotypes (A, B, C 1 , C 2 , D, E, F, G), which have protease activity targeting the pre-synaptic neuroreceptor soluble N-ethylmaleimide-sensitive factor (NSF) attachment protein receptor (SNARE) complex responsible for neutortransmitter (acetylcholine) release [81,82].…”

“…BoNT has seven distinct serotypes (A, B, C 1 , C 2 , D, E, F, G), which have protease activity targeting the pre-synaptic neuroreceptor soluble N-ethylmaleimide-sensitive factor (NSF) attachment protein receptor (SNARE) complex responsible for neutortransmitter (acetylcholine) release [81,82]. This SNARE complex consists of SNARE domains contributed by SNAP25 (hydrolysed by serotypes E, C, A), Synaptobrevin or vesicle-associated membrane protein (VAMP) (hydrolysed by serotypes G,B,D,F) and Syntaxin 1 (hydrolysed by serotype C) proteins [81]. Cleavage of these target molecules prevents neurotransmitter release.…”

The translocation domain of botulinum neurotoxin A moderates the propensity of the catalytic domain to interact with membranes at acidic pH

“…The three domains are critical for cell intoxication by BoNTs. H C allows recognition of neuronal cells by a double anchorage to a ganglioside and a protein receptor [8][9][10][11]. Following binding to its receptors, BoNT is internalized through clathrin-dynamin mediated endocytosis of recycling neurosecretion vesicles [12].…”