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.
Highlights
Clostridium sordellii produces two major virulence factors, the hemorrhagic toxin and the lethal toxin (LT),1 which are causally involved in diarrhea and enterotoxemia in domestic animals and in gas gangrene in man [1, 2]
C. sordellii lethal toxin belongs to the family of large clostridial cytotoxins, which is characterized by a single-chain structure and a molecular mass of 250 –300 kDa [11]
toxin A (ToxA) and toxin B (ToxB), which are coexpressed by pathogenic C. difficile strains, show an identity of 49% (63% homology) at the amino acid level [27]
Summary
Clostridium sordellii produces two major virulence factors, the hemorrhagic toxin and the lethal toxin (LT),1 which are causally involved in diarrhea and enterotoxemia in domestic animals and in gas gangrene in man [1, 2]. We reported that ToxA and ToxB from C. difficile are monoglucosyltransferases that selectively modify the low molecular mass GTP-binding proteins of the Rho subfamily [12, 13], whereas other members of the Ras superfamily are not substrates.
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