PMID:20696758

Citation	Nam, HJ, Kang, JK, Kim, SK, Ahn, KJ, Seok, H, Park, SJ, Chang, JS, Pothoulakis, C, Lamont, JT and Kim, H (2010) Clostridium difficile toxin A decreases acetylation of tubulin, leading to microtubule depolymerization through activation of histone deacetylase 6, and this mediates acute inflammation. J. Biol. Chem. 285:32888-96
Abstract	Clostridium difficile toxin A is known to cause actin disaggregation through the enzymatic inactivation of intracellular Rho proteins. Based on the rapid and severe cell rounding of toxin A-exposed cells, we speculated that toxin A may be involved in post-translational modification of tubulin, leading to microtubule instability. In the current study, we observed that toxin A strongly reduced α-tubulin acetylation in human colonocytes and mouse intestine. Fractionation analysis demonstrated that toxin A-induced α-tubulin deacetylation yielded monomeric tubulin, indicating the presence of microtubule depolymerization. Inhibition of the glucosyltransferase activity against Rho proteins of toxin A by UDP-2',3'-dialdehyde significantly abrogated toxin A-induced α-tubulin deacetylation. In colonocytes treated with trichostatin A (TSA), an inhibitor of the HDAC6 tubulin deacetylase, toxin A-induced α-tubulin deacetylation and loss of tight junction were completely blocked. Administration of TSA also attenuated proinflammatory cytokine production, mucosal damage, and epithelial cell apoptosis in mouse intestine exposed to toxin A. These results suggest that toxin A causes microtubule depolymerization by activation of HDAC6-mediated tubulin deacetylation. Indeed, blockage of HDAC6 by TSA markedly attenuates α-tubulin deacetylation, proinflammatory cytokine production, and mucosal damage in a toxin A-induced mouse enteritis model. Tubulin deacetylation is an important component of the intestinal inflammatory cascade following toxin A-mediated Rho inactivation in vitro and in vivo.
Links	PubMed PMC2963380 Online version:10.1074/jbc.M110.162743
Keywords	Acetylation/drug effects; Acute Disease; Animals; Apoptosis/drug effects; Bacterial Toxins/toxicity; Cell Line; Colon/metabolism; Colon/pathology; Cytokines/biosynthesis; Enteritis/chemically induced; Enteritis/drug therapy; Enteritis/metabolism; Enterotoxins/toxicity; Enzyme Activation/drug effects; Epithelial Cells/metabolism; Histone Deacetylase Inhibitors/pharmacology; Histone Deacetylases/metabolism; Humans; Hydroxamic Acids/pharmacology; Inflammation/chemically induced; Inflammation/drug therapy; Inflammation/metabolism; Intestinal Mucosa/metabolism; Intestinal Mucosa/pathology; Mice; Microtubules/metabolism; Protein Processing, Post-Translational/drug effects; Tubulin/genetics; Tubulin/metabolism; Uridine Diphosphate/analogs & derivatives; Uridine Diphosphate/pharmacology; rho GTP-Binding Proteins/metabolism
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
CLODI:TOXA		GO:0090044: positive regulation of tubulin deacetylation	ECO:0000314:		P		Fig. 1A. Note that the GO term cannot beGO:0090042 because ToxA mediates tubulin deacetylation via HDAC6.	complete

References

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