Hsp90 is involved in the entry of clostridial neurotoxins into the cytosol of nerve terminals

• DOI: 10.1111/cmi.12647
• Publication Date: 2016-07-12T21:32:36Z
• Authors: Domenico Azarnia ...; Marco Pirazzini; Oneda Leka; Andrea Mattarei; Florigio Lista; Thomas Binz; Ornella Rossetto; Cesare Montecucco
• Keywords: Geldanamycin; Chaperone (clinical)

Botulinum and tetanus neurotoxins are the most toxic substances known form growing family of clostridial neurotoxins. They composed a metalloprotease light chain (L), linked via disulfide bond to heavy (H). H mediates binding nerve terminals membrane translocation L into cytosol where their substrates, three SNARE proteins, localised. is accompanied by unfolding, it has be reduced reacquire native fold exert its neurotoxicity. The Thioredoxin reductase-Thioredoxin system responsible for reduction, but unknown whether refolding spontaneous or aided host chaperones. Here we report that geldanamycin, specific inhibitor heat shock protein 90, hampers after completely prevents cleavage SNAREs. We also found geldanamycin strongly synergises with PX-12, an thioredoxin, suggesting processes interchain reduction strictly coupled. Indeed 90 physically interact on synaptic vesicle they orchestrate chaperone-redox machinery which exploited deliver catalytic part cytosol.