Cleavage of E-cadherin: a mechanism for disruption of the intestinal epithelial barrier by Candida albicans

Transl Res. 2007 Apr;149(4):211-22. doi: 10.1016/j.trsl.2006.11.006.


To investigate how intestinal epithelial cells respond to contact with Candida albicans, an organism able to invade the bloodstream via the gastrointestinal tract, we focused on the junction proteins occludin, E-cadherin, and desmoglein-2. The levels of these 3 junction proteins were reduced in lysates of human intestinal epithelial monolayers (Caco-2) after a 24-h inoculation with C. albicans, compared with lysates from Saccharomyces cerevisiae-inoculated monolayers. Treatment with pepstatin A did not change the effect of C. albicans on full-length occludin, desmoglein-2, and E-cadherin; however, pepstatin A enhanced the accumulation of a 35-kDa fragment derived from the intracellular portion of E-cadherin. This 35-kDa fragment also accumulated in the presence of gamma-secretase inhibitors. These observations suggest that enhancement of E-cadherin cleavage by C. albicans generates an intracellular E-cadherin fragment that can serve as a substrate for gamma-secretase. An 89-kDa extracellular fragment of E-cadherin was detected in supernatants of C. albicans-inoculated monolayers; this cleavage event was insensitive to both pepstatin A and gamma-secretase inhibitors. Transepithelial electrical resistance, a measure of monolayer integrity, decreased significantly and synchronously with increased generation of the 89-kDa extracellular E-cadherin fragment. Cleavage of E-cadherin may destabilize the homotypic interactions between adjacent epithelial cells and could contribute to loss of monolayer integrity. These experiments identify 2 E-cadherin cleavage events that are enhanced by contact with C. albicans: an intracellular cleavage event that generates a substrate for gamma-secretase and an extracellular cleavage event that is temporally associated with an increase in monolayer permeability.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyloid Precursor Protein Secretases / antagonists & inhibitors
  • Amyloid Precursor Protein Secretases / metabolism
  • Caco-2 Cells
  • Cadherins / antagonists & inhibitors
  • Cadherins / chemistry*
  • Cadherins / metabolism*
  • Candida albicans / physiology*
  • Desmoglein 2 / antagonists & inhibitors
  • Electric Impedance
  • Extracellular Fluid / metabolism
  • Humans
  • Intestinal Mucosa / metabolism*
  • Intestinal Mucosa / microbiology*
  • Intestinal Mucosa / physiology
  • Intracellular Membranes / metabolism
  • Membrane Proteins / antagonists & inhibitors
  • Molecular Weight
  • Occludin
  • Pepstatins / pharmacology
  • Peptide Fragments / metabolism
  • Permeability
  • Protease Inhibitors / pharmacology
  • Saccharomyces cerevisiae / physiology


  • Cadherins
  • Desmoglein 2
  • Membrane Proteins
  • OCLN protein, human
  • Occludin
  • Pepstatins
  • Peptide Fragments
  • Protease Inhibitors
  • Amyloid Precursor Protein Secretases
  • pepstatin