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Autoproteolytic cleavage mediates cytotoxicity of Clostridium difficile toxin A.
MedLine Citation:
PMID:  21046073     Owner:  NLM     Status:  In-Data-Review    
Abstract/OtherAbstract:
Toxin A and toxin B from Clostridium difficile are the causative agents of the antibiotic-associated pseudomembranous colitis. They are of an A/B structure type and possess inositol hexakisphosphate-inducible autoproteolytic activity to release their glucosyltransferase domain to the cytoplasm of target cells. In this study, we investigated the effect of extracellular and intracellular autoproteolytic cleavage on the function of TcdA. Extracellular cleavage led to functional inactivation albeit TcdA was less susceptible to inositol hexakisphosphate-induced autoproteolysis than TcdB. A non-cleavable TcdA mutant (TcdA A541 G542 A543) was generated to investigate whether autoproteolysis is a prerequisite for intracellular function of TcdA. Although the EC(50) regarding cell rounding was about 75-fold reduced in short-term assay, non-cleavable TcdA was able to induce complete cell rounding and apoptosis after 36 h comparable to wildtype TcdA when continuously present. Studies with limited uptake of toxins revealed progressive Rac1 glucosylation and complete cell rounding for TcdA, whereas the effect induced by non-cleavable TcdA was reversible. These findings argue for cytosolic accumulation of the released glucosyltransferase domain of wild-type TcdA and rapid degradation of the non-cleavable TcdA. In summary, extracellular cleavage functionally inactivates TcdA (and TcdB), whereas intracellular autoproteolytic cleavage is not essential for function of TcdA but defines its potency.
Authors:
Isa Kreimeyer; Friederike Euler; Alexander Marckscheffel; Helma Tatge; Andreas Pich; Alexandra Olling; Janett Schwarz; Ingo Just; Ralf Gerhard
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Publication Detail:
Type:  Journal Article     Date:  2010-11-03
Journal Detail:
Title:  Naunyn-Schmiedeberg's archives of pharmacology     Volume:  383     ISSN:  1432-1912     ISO Abbreviation:  Naunyn Schmiedebergs Arch. Pharmacol.     Publication Date:  2011 Mar 
Date Detail:
Created Date:  2011-02-21     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0326264     Medline TA:  Naunyn Schmiedebergs Arch Pharmacol     Country:  Germany    
Other Details:
Languages:  eng     Pagination:  253-62     Citation Subset:  IM    
Affiliation:
Institut für Toxikologie, Medizinische Hochschule, Carl-Neuberg-Str. 1, 30625, Hannover, Germany.
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