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J. Biol. Chem., Vol. 275, Issue 25, 18704-18711, June 23, 2000
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From the The actin-ADP-ribosylating binary
Clostridium botulinum C2 toxin consists of two individual
proteins, the binding/translocation component C2II and the enzyme
component C2I. To elicit its cytotoxic action, C2II binds to a receptor
on the cell surface and mediates cell entry of C2I via
receptor-mediated endocytosis. Here we report that binding of C2II to
the surface of target cells requires cleavage of C2II by trypsin.
Trypsin cleavage causes oligomerization of the activated C2II (C2IIa)
to give SDS-stable heptameric structures, which exhibit a
characteristic annular or horseshoe shape and form channels in lipid
bilayer membranes. Cytosolic delivery of the enzyme component C2I is
blocked by bafilomycin but not by brefeldin A or nocodazole, indicating
uptake from an endosomal compartment and requirement of endosomal
acidification for cell entry. In the presence of C2IIa and C2I, short
term acidification of the extracellular medium (pH 5.4) allows C2I to
enter the cytosol directly. Our data indicate that entry of C2 toxin
into cells involves (i) activation of C2II by trypsin-cleavage, (ii)
oligomerization of cleaved C2IIa to heptamers, (iii) binding of the
C2IIa oligomers to the carbohydrate receptor on the cell surface and
assembly with C2I, (iv) receptor-mediated endocytosis of both C2
components into endosomes, and finally (v) translocation and release of
C2I into the cytosol after acidification of the endosomal compartment.
Cellular Uptake of Clostridium botulinum C2 Toxin
Requires Oligomerization and Acidification*
,,
,,
Institut für Pharmakologie und
Toxikologie der Albert-Ludwigs-Universität Freiburg,
Hermann-Herder-Str. 5, D-79104 Freiburg, Germany,
¶ Max-Delbrück-Zentrum für Molekulare Medizin,
Robert-Rössle-Str. 10, D-13125 Berlin, Germany, Department
of Biophysical Chemistry, University of Groningen, Nijenborgh 4, NL-9747 AG Groningen, The Netherlands, and ** Lehrstuhl für
Biotechnologie, Theodor-Boveri-Institut (Biozentrum) der
Universität Würzburg, Am Hubland,
D-97074 Würzburg, Germany
*
This study was supported by the Deutsche
Forschungsgemeinschaft (Sonderforschungsbereich 388) and by the Fonds
der Chemischen 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.
To whom correspondence should be addressed: Institut für
Pharmakologie und Toxikologie, Hermann-Herder-Str. 5, D-79104 Freiburg, Germany. Tel.: 49-761-2035301; Fax: 49-761-2035311; E-mail:
aktories@uni-freiburg.de.
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