The thioredoxin reductase-thioredoxin system is involved in the entry of tetanus and botulinum neurotoxins in the cytosol of nerve terminals

► Auranofin inhibits thioredoxins reductase activity in neuronal culture. ► Auranofin blocks tetanus and botulinum neurotoxins in neuronal culture. ► Inhibition of thioredoxin reductase prevents interchain disulphide reduction. ► Thioredoxin reductase is a new target for novel antitoxins inhibitors. ► Auranofin is proposed as a lead molecule for new inhibitors. 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.