Thioredoxin reductase inhibitor auranofin prevents membrane transport of diphtheria toxin into the cytosol and protects human cells from intoxication.
During cellular uptake, diphtheria toxin delivers its catalytic domain DTA from acidified endosomes into the cytosol, which requires reduction of the disulfide linking DTA to the transport domain. In vitro, thioredoxin reduces this disulfide and thioredoxin reductase (TrxR) is part of a cytosolic complex facilitating DTA-translocation. We found that the TrxR-specific inhibitor auranofin prevented DTA delivery into the cytosol and intoxication of HeLa cells with diphtheria toxin, offering perspectives for novel pharmacological strategies against diphtheria.
Institute of Pharmacology and Toxicology, University of Ulm Medical Center, Germany.
Leonie
L
Schnell
Institute of Pharmacology and Toxicology, University of Ulm Medical Center, Germany.
Lydia
L
Dmochewitz-Kück
Institute of Pharmacology and Toxicology, University of Ulm Medical Center, Germany.
Peter
P
Feigl
Department of Biomedical Sciences, University of Padova, Italy. Electronic address: cesare.montecucco@gmail.com.
Cesare
C
Montecucco
Institute of Pharmacology and Toxicology, University of Ulm Medical Center, Germany. Electronic address: holger.barth@uni-ulm.de.
Holger
H
Barth
D001310:Auranofin / Q000494:pharmacology*; D001692:Biological Transport / Q000187:drug effects*; D003600:Cytosol / Q000378:metabolism; D004167:Diphtheria Toxin / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D006863:Hydrogen-Ion Concentration; D020011:Protective Agents / Q000494:pharmacology*; D013880:Thioredoxin-Disulfide Reductase / Q000037:antagonists & inhibitors*
D004167:Diphtheria Toxin; D020011:Protective Agents; D001310:Auranofin; D013880:Thioredoxin-Disulfide Reductase
Auranofin; Cellular uptake; Diphtheria toxin; Endosome; Membrane translocation; Thioredoxin reductase