title: The thioredoxin reductase-thioredoxin system is involved in the entry of tetanus and botulinum neurotoxins in the cytosol of nerve terminals.
abstract: Tetanus and botulinum neurotoxins cause paralysis by cleaving SNARE proteins within the cytosol of nerve terminals. They are endocytosed inside acidic vesicles and the pH gradient across the membrane drives the translocation of their metalloprotease L domain in the cytosol. This domain is linked to the rest of the molecule by a single interchain disulfide bridge that has to be reduced on the cytosolic side of the membrane to free its enzymatic activity. By using specific inhibitors of the various cytosolic protein disulfides reducing systems, we show here that the NADPH-thioredoxin reductase-thioredoxin redox system is the main responsible for this disulfide reduction. In addition, we indicate auranofin, as a possible basis for the design of novel inhibitors of these neurotoxins.
authors.affiliation: Dipartimento di Scienze Biomediche and Istituto CNR di Neuroscienze, Università di Padova, Viale G. Colombo 3, 35131 Padova, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Pirazzini
authors.forename: Fulvio
authors.initials: F
authors.lastname: Bordin
authors.forename: Ornella
authors.initials: O
authors.lastname: Rossetto
authors.forename: Clifford C
authors.initials: CC
authors.lastname: Shone
authors.forename: Thomas
authors.initials: T
authors.lastname: Binz
authors.forename: Cesare
authors.initials: C
authors.lastname: Montecucco
mesh_terms: D000818:Animals; D001310:Auranofin / Q000494:pharmacology; D001693:Biological Transport, Active; D001905:Botulinum Toxins / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000633:toxicity; D002478:Cells, Cultured; D003600:Cytosol / Q000378:metabolism; D004705:Endocytosis; D004791:Enzyme Inhibitors / Q000494:pharmacology; D008297:Male; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors / Q000378:metabolism; D051379:Mice; D017729:Presynaptic Terminals / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D050600:SNARE Proteins / Q000378:metabolism; D013744:Tetanus Toxin / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000633:toxicity; D013880:Thioredoxin-Disulfide Reductase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013879:Thioredoxins / Q000378:metabolism*
chemical_list: D004791:Enzyme Inhibitors; D050600:SNARE Proteins; D013744:Tetanus Toxin; D001310:Auranofin; D013879:Thioredoxins; D013880:Thioredoxin-Disulfide Reductase; D008666:Metalloendopeptidases; C093556:zinc-endopeptidase, tetanus neurotoxin; D001905:Botulinum Toxins