Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: EC:4.1.2.42 (
DTA
)
1,693
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Bacillus anthracis lethal toxin consists of the protective antigen (PA) and the metalloprotease lethal factor (LF). During cellular uptake PA forms pores in membranes of endosomes, and unfolded LF translocates through the pores into the cytosol. We have investigated whether host cell chaperones facilitate translocation of LF and the fusion protein LF(N)
DTA
. LF(N) mediates uptake of LF(N)
DTA
into the cytosol, where
DTA
, the catalytic domain of diphtheria toxin, ADP-ribosylates elongation factor-2, allowing for detection of small amounts of translocated LF(N)
DTA
. Cyclosporin A, which inhibits peptidyl-prolyl cis/trans isomerase activity of cyclophilins, and radicicol, which inhibits
Hsp90
activity, prevented uptake of LF(N)
DTA
into the cytosol of CHO-K1 cells and protected cells from intoxication by LF(N)
DTA
/PA. Both inhibitors, as well as an antibody against cyclophilin A blocked the release of active LF(N)
DTA
from endosomal vesicles into the cytosol in vitro. In contrast, the inhibitors did not inhibit cellular uptake of LF. In vitro, cyclophilin A and
Hsp90
bound to LF(N)
DTA
and
DTA
but not to LF, implying that
DTA
determines this interaction. In conclusion, cyclophilin A and
Hsp90
facilitate translocation of LF(N)
DTA
, but not of LF, across endosomal membranes, and thus they function selectively in promoting translocation of certain proteins, but not of others.
...
PMID:Role of CypA and Hsp90 in membrane translocation mediated by anthrax protective antigen. 2094 44
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.
...
PMID:The Hsp90 machinery facilitates the transport of diphtheria toxin into human cells. 2837 14
