Bacteroides fragilis toxin stimulates intestinal epithelial cell shedding and γ-secretase-dependent E-cadherin cleavage

Shaoguang Wu, Ki Jong Rhee, Ming Zhang, Augusto Franco, Cynthia L. Sears

Research output: Contribution to journalArticle

85 Citations (Scopus)

Abstract

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 β-catenin-T-cell-factor nuclear signaling. γ-Secretase (or presenilin-1) is an intramembrane cleaving protease and is a positive regulator of E-cadherin cleavage and a negative regulator of β-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 γ-secretase blocked toxin-induced proteolysis of the 33 kDa intracellular E-cadherin domain causing cell membrane retention of a distinct β-catenin pool without diminishing toxin-induced cell proliferation. Unexpectedly, γ-secretase positively regulated basal cell proliferation dependent on the β-catenin-T-cell-factor complex. We conclude that toxin induces step-wise cleavage of E-cadherin, which is dependent on toxin metalloprotease and γ-secretase. Our results suggest that differentially regulated β-catenin pools associate with the E-cadherin-γ-secretase adherens junction complex; one pool regulated by γ-secretase is important to intestinal epithelial cell homeostasis.

Original languageEnglish
Pages (from-to)1944-1952
Number of pages9
JournalJournal of cell science
Volume120
Issue number11
DOIs
Publication statusPublished - 2007 Jun 1

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Amyloid Precursor Protein Secretases
Cadherins
Catenins
Epithelial Cells
TCF Transcription Factors
Cell Proliferation
Metalloproteases
Presenilin-1
Adherens Junctions
Bacteroides fragilis
Bacteroides fragilis toxin
Matrix Metalloproteinases
Proteolysis
Membrane Proteins
Colon
Homeostasis
Peptide Hydrolases
Cell Membrane

All Science Journal Classification (ASJC) codes

  • Cell Biology

Cite this

Wu, Shaoguang ; Rhee, Ki Jong ; Zhang, Ming ; Franco, Augusto ; Sears, Cynthia L. / Bacteroides fragilis toxin stimulates intestinal epithelial cell shedding and γ-secretase-dependent E-cadherin cleavage. In: Journal of cell science. 2007 ; Vol. 120, No. 11. pp. 1944-1952.
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abstract = "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 β-catenin-T-cell-factor nuclear signaling. γ-Secretase (or presenilin-1) is an intramembrane cleaving protease and is a positive regulator of E-cadherin cleavage and a negative regulator of β-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 γ-secretase blocked toxin-induced proteolysis of the 33 kDa intracellular E-cadherin domain causing cell membrane retention of a distinct β-catenin pool without diminishing toxin-induced cell proliferation. Unexpectedly, γ-secretase positively regulated basal cell proliferation dependent on the β-catenin-T-cell-factor complex. We conclude that toxin induces step-wise cleavage of E-cadherin, which is dependent on toxin metalloprotease and γ-secretase. Our results suggest that differentially regulated β-catenin pools associate with the E-cadherin-γ-secretase adherens junction complex; one pool regulated by γ-secretase is important to intestinal epithelial cell homeostasis.",
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Bacteroides fragilis toxin stimulates intestinal epithelial cell shedding and γ-secretase-dependent E-cadherin cleavage. / Wu, Shaoguang; Rhee, Ki Jong; Zhang, Ming; Franco, Augusto; Sears, Cynthia L.

In: Journal of cell science, Vol. 120, No. 11, 01.06.2007, p. 1944-1952.

Research output: Contribution to journalArticle

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