Bacteroides fragilis enterotoxin cleaves the zonula adherens protein, E-cadherin

Strains of Bacteroides fragilis associated with diarrheal disease (enteroto xigenic B. fragilis) produce a 20-kDa zinc-dependent metalloprotease toxin (B. fragilis enterotoxin; BFT) that reversibly stimulates chloride secretio n and alters tight junctional function in polarized intestinal epithelial c ells. BFT alters cellular morphology and physiology most potently and rapid ly when placed on the basolateral membrane of epithelial cells, suggesting that the cellular substrate for BFT may be present on this membrane. Herein , we demonstrate that BFT specifically cleaves within 1 min the extracellul ar domain of the zonula adherens protein, E-cadherin. Cleavage of E-cadheri n by BFT is ATP-independent and essential to the morphologic and physiologi c activity of BFT. However, the morphologic changes occurring in response t o BFT are dependent on target-cell ATP. E-cadherin is shown here to be a ce llular substrate for a bacterial toxin and represents the identification of a mechanism of action, cell-surface proteolytic activity, for a bacterial toxin.