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Clostridium difficile toxin A induces expression of the stress-induced early gene product RhoB

Ralf Gerhard1, Helma Tatge, Harald Genth

  • 1Institute of Toxicology, Hannover Medical School, Carl-Neuberg-Strasse 1, 30625 Hannover, Germany. gerhard.ralf@mh-hannover.de

The Journal of Biological Chemistry
|November 9, 2004
PubMed

Insights

Clostridium difficile toxin A inactivates Rho GTPases but surprisingly also generates active RhoB. This active RhoB likely contributes to cellular changes observed during toxin A treatment.

Area of Science:

  • Cell Biology
  • Microbiology
  • Molecular Biology

Background:

  • Clostridium difficile toxin A (TcdA) is a potent virulence factor.
  • TcdA monoglucosylates Rho GTPases, leading to actin cytoskeleton disruption.
  • The cellular response to TcdA, particularly regarding Rho GTPase expression, requires further elucidation.

Purpose of the Study:

  • To investigate the effect of TcdA on Rho GTPase expression, specifically RhoB.
  • To identify the signaling pathways involved in TcdA-induced RhoB up-regulation.
  • To determine the functional state of RhoB following TcdA treatment.

Main Methods:

  • cDNA microarray analysis to identify differentially expressed genes.
  • Cell culture (CaCo-2, HT29, MDCK, NIH 3T3) and treatment with TcdA.
  • Inhibition studies using cycloheximide and p38 MAPK inhibitor (SB202190).
  • Assessment of RhoB activity using C3bot-catalyzed ADP-ribosylation and pull-down assays.

Main Results:

  • TcdA treatment significantly up-regulated the immediate early gene rhoB in various cell types.
  • RhoB up-regulation was dependent on de novo protein synthesis and involved the p38 MAPK pathway.
  • A significant pool of active RhoB was detected in TcdA-treated cells, indicating partial glucosylation.
  • Active RhoB levels were higher in TcdA-treated cells compared to controls.

Conclusions:

  • TcdA not only inactivates RhoA, Rac1, and Cdc42 but also induces the generation of active RhoB.
  • The p38 MAPK pathway mediates the stress response leading to RhoB expression.
  • The newly generated active RhoB likely plays a role in the cellular pathology induced by TcdA.

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