title: Cleavage of E-cadherin: a mechanism for disruption of the intestinal epithelial barrier by Candida albicans.
abstract: 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.
authors: Department of Microbiology, Yale University, New Haven, CT 06520, USA.
authors: Charlotte F
authors: CF
authors: Frank
authors: Margaret K
authors: MK
authors: Hostetter
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors / Q000378:metabolism; D018938:Caco-2 Cells; D015820:Cadherins / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism*; D002176:Candida albicans / Q000502:physiology*; D051301:Desmoglein 2 / Q000037:antagonists & inhibitors; D017097:Electric Impedance; D045604:Extracellular Fluid / Q000378:metabolism; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism* / Q000382:microbiology* / Q000502:physiology; D007425:Intracellular Membranes / Q000378:metabolism; D008565:Membrane Proteins / Q000037:antagonists & inhibitors; D008970:Molecular Weight; D062793:Occludin; D010436:Pepstatins / Q000494:pharmacology; D010446:Peptide Fragments / Q000378:metabolism; D010539:Permeability; D011480:Protease Inhibitors / Q000494:pharmacology; D012441:Saccharomyces cerevisiae / Q000502:physiology
chemical_list: D015820:Cadherins; D051301:Desmoglein 2; D008565:Membrane Proteins; C568985:OCLN protein, human; D062793:Occludin; D010436:Pepstatins; D010446:Peptide Fragments; D011480:Protease Inhibitors; D053829:Amyloid Precursor Protein Secretases; C031375:pepstatin