Inactivation of Ras by Clostridium sordellii Lethal Toxin-catalyzed Glucosylation (*)
- From the Institut für Pharmakologie und Toxikologie der Universität Freiburg, Hermann-Herder-Straße 5, D-79104 Freiburg, Germany Laboratoire Toxinologie Bacterienne, Faculté de Médecine, Université Louis-Pasteur, F-67000 Strasbourg, France
- § To whom correspondence should be addressed: Tel.: 49-761-203-5316; Fax: 49-761-203-5311.
Abstract
The lethal toxin (LT) from Clostridium sordellii belongs to the family of large clostridial cytotoxins causing morphological alterations in cultured cell lines accompanied by destruction of the actin cytoskeleton. C. sordellii LT exhibits 90% homology to Clostridium difficile toxin B, which has been recently identified as a monoglucosyltransferase (Just, I., Selzer, J., Wilm, M., von Eichel-Streiber, C., Mann, M., and Aktories, K.(1995) Nature 375, 500-503). We report here that LT too is a glucosyltransferase, which uses UDP-glucose as cosubstrate to modify low molecular mass GTPases. LT selectively modifies Rac and Ras, whereas the substrate specificity of toxin B is confined to the Rho subfamily proteins Rho, Rac, and Cdc42, which participate in the regulation of the actin cytoskeleton. In Rac, both toxin B and LT share the same acceptor amino acid, threonine 35. Glucosylation of Ras by LT results in inhibition of the epidermal growth factor-stimulated p42/p44 MAP-kinase signal pathway. LT is the first bacterial toxin to inactivate Ras in intact cells.
Footnotes
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↵* This work was supported by the Deutsche Forschungsgemeinschaft (Projects Ju231/3-1 and SFB388). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore by hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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↵1 The abbreviations used are:
- LT
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C. sordellii lethal toxin
- ToxA
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C. difficile toxin A
- ToxB
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C. difficile toxin B
- EGF
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epidermal growth factor
- PAGE
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polyacrylamide gel electrophoresis
- MAP
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mitogen-activated protein.
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- Received December 20, 1995.
- Revision received February 12, 1996.
