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First published online 15 May 2007
doi: 10.1242/jcs.03455

Journal of Cell Science 120, 1944-1952 (2007)
Published by The Company of Biologists 2007
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Research Article

Bacteroides fragilis toxin stimulates intestinal epithelial cell shedding and {gamma}-secretase-dependent E-cadherin cleavage

Shaoguang Wu1, Ki-Jong Rhee1, Ming Zhang1, Augusto Franco1 and Cynthia L. Sears1,2,*

1 Division of Infectious Diseases, Department of Medicine, Johns Hopkins University School of Medicine, 1550 Orleans St, CRB2 Bldg Suite 1M.05, Baltimore, MD 21231, USA
2 Division of Gastroenterology, Department of Medicine, Johns Hopkins University School of Medicine, 1550 Orleans St, CRB2 Bldg Suite 1M.05, Baltimore, MD 21231, USA

* Author for correspondence (e-mail: csears{at}jhmi.edu)

Accepted 10 April 2007

Enterotoxigenic Bacteroides fragilis – organisms that live in the colon – secrete a metalloprotease toxin, B. fragilis toxin. This toxin binds to a specific intestinal epithelial cell receptor and stimulates cell proliferation, which is dependent, in part, on E-cadherin degradation and beta-catenin–T-cell-factor nuclear signaling. {gamma}-Secretase (or presenilin-1) is an intramembrane cleaving protease and is a positive regulator of E-cadherin cleavage and a negative regulator of beta-catenin signaling. Here we examine the mechanistic details of toxin-initiated E-cadherin cleavage. B. fragilis toxin stimulated shedding of cell membrane proteins, including the 80 kDa E-cadherin ectodomain. Shedding of this domain required biologically active toxin and was not mediated by MMP-7, ADAM10 or ADAM17. Inhibition of {gamma}-secretase blocked toxin-induced proteolysis of the 33 kDa intracellular E-cadherin domain causing cell membrane retention of a distinct beta-catenin pool without diminishing toxin-induced cell proliferation. Unexpectedly, {gamma}-secretase positively regulated basal cell proliferation dependent on the beta-catenin–T-cell-factor complex. We conclude that toxin induces step-wise cleavage of E-cadherin, which is dependent on toxin metalloprotease and {gamma}-secretase. Our results suggest that differentially regulated beta-catenin pools associate with the E-cadherin–{gamma}-secretase adherens junction complex; one pool regulated by {gamma}-secretase is important to intestinal epithelial cell homeostasis.

Key words: Bacteroides fragilis, Bacteroides fragilis toxin, Metalloproteases, E-cadherin, ADAM, {gamma}-secretase


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