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J. Biol. Chem., Vol. 276, Issue 14, 10670-10676, April 6, 2001
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From the Clostridium difficile toxin B (269 kDa), which is one of the causative agents of antibiotic-associated
diarrhea and pseudomembranous colitis, inactivates Rho GTPases by
glucosylation. Here we studied the uptake and membrane interaction of
the toxin with eukaryotic target cells. Bafilomycin A1, which prevents
acidification of endosomal compartments, blocked the cellular uptake of
toxin B in Chinese hamster ovary cells cells. Extracellular
acidification (pH
Low pH-induced Formation of Ion Channels by Clostridium
difficile Toxin B in Target Cells*
,,,¶
Institut für Experimentelle und
Klinische Pharmakologie und Toxikologie der
Albert-Ludwigs-Universität Freiburg, D-79104 Freiburg, Germany,
and § Lehrstuhl für Biotechnologie,
Theodor-Boveri-Institut (Biozentrum) der Universität
Würzburg, Am Hubland, D-97074 Würzburg, Germany
5.2) induced uptake of toxin B into the
cytosol even in the presence of bafilomycin A1. Toxin B increased
86Rb+ release when preloaded Chinese hamster
ovary cells were exposed to low pH (pH 5.6) for 5 min. Release
of 86Rb+ depended on the concentration of toxin
B and on the pH of the extracellular medium. An antibody directed
against the holotoxin prevented channel formation, whereas an antibody
against the N-terminal enzyme domain was without effect. The
N-terminally truncated toxin B fragment consisting of amino acids
547-2366 increased 86Rb+ efflux when cells
were exposed to low pH. Toxin B also induced pH-dependent
channel formation in artificial lipid bilayer membranes. Clostridium sordellii lethal toxin, another member of the
family of large clostridial cytotoxins, also induced increased
86Rb+ release at low pH. The results
suggest that large clostridial cytotoxins including C. difficile toxin B and C. sordellii lethal toxin
undergo structural changes at low pH of endosomes that are accompanied
by membrane insertion and channel formation.
*
This work was supported by the Deutsche
Forschungsgemeinschaft (Sonderforschungsbereich 388 and 487) and by the
Fonds of the Chemische Industrie.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
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