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Abstract:
Diphtheria toxin kills human cells because it delivers its enzyme domain
DTA into their cytosol where it inhibits protein synthesis. After
receptor-mediated uptake of the toxin, DTA translocates from acidic
endosomes into the cytosol, which might be assisted by host cell
factors. Here we investigated the role of Hsp90 and its co-chaperones
during the uptake of native diphtheria toxin into human cells and
identified the components of the Hsp90 machinery including Hsp90, Hsp70,
Cyp40 and the FK506 binding proteins FKBP51 and FKBP52 as DTA binding
partners. Moreover, pharmacological inhibition of the chaperone activity
of Hsp90 and Hsp70 and of the peptidyl-prolyl cis/trans isomerase
(PPIase) activity of Cyps and FKBPs protected cells from intoxication
with diphtheria toxin and inhibited the pH-dependent trans-membrane
transport of DTA into the cytosol. In conclusion, these host cell
factors facilitate toxin uptake into human cells, which might lead to
development of novel therapeutic strategies against diphtheria.
