title: Mucosal tissue invasion by Candida albicans is associated with E-cadherin degradation, mediated by transcription factor Rim101p and protease Sap5p.
abstract: The ability of Candida albicans to invade mucosal tissues is a major virulence determinant of this organism; however, the mechanism of invasion is not understood in detail. Proteolytic breakdown of E-cadherin, the major protein in epithelial cell junctions, has been proposed as a mechanism of invasion of certain bacteria in the oral mucosa. The objectives of this study were (i) to assess whether C. albicans degrades E-cadherin expressed by oral epithelial cells in vitro; (ii) to compare the abilities of strains with different invasive potentials to degrade this protein; and (iii) to investigate fungal virulence factors responsible for E-cadherin degradation. We found that while E-cadherin gene expression was not altered, E-cadherin was proteolytically degraded during the interaction of oral epithelial cells with C. albicans. Moreover, C. albicans-mediated degradation of E-cadherin was completely inhibited in the presence of protease inhibitors. Using a three-dimensional model of the human oral mucosa, we found that E-cadherin was degraded in localized areas of tissue invasion by C. albicans. An invasion-deficient rim101-/rim101- strain was deficient in degradation of E-cadherin, and this finding suggested that proteases may depend on Rim101p for expression. Indeed, reverse transcription-PCR data indicated that expression of the SAP4, SAP5, and SAP6 genes is severely reduced in the rim101-/rim101- mutant. These SAP genes are functional Rim101p targets, because engineered expression of SAP5 in the rim101-/rim101- strain restored E-cadherin degradation and invasion in the mucosal model. Our data support the hypothesis that there is a mechanism by which C. albicans invades mucosal tissues by promoting the proteolytic degradation of E-cadherin in epithelial adherens junctions.
authors.affiliation: Department of Periodontology, School of Dental Medicine, University of Connecticut, 263 Farmington Ave., Farmington, CT 06030-1710, USA. cvillar@uchc.edu
authors.forename: C C
authors.initials: CC
authors.lastname: Villar
authors.forename: H
authors.initials: H
authors.lastname: Kashleva
authors.forename: C J
authors.initials: CJ
authors.lastname: Nobile
authors.forename: A P
authors.initials: AP
authors.lastname: Mitchell
authors.forename: A
authors.initials: A
authors.lastname: Dongari-Bagtzoglou
mesh_terms: D022005:Adherens Junctions / Q000378:metabolism; D016282:Aspartic Acid Endopeptidases / Q000235:genetics / Q000378:metabolism*; D015820:Cadherins / Q000235:genetics / Q000378:metabolism*; D002176:Candida albicans / Q000235:genetics / Q000472:pathogenicity*; D002180:Candidiasis, Oral / Q000382:microbiology / Q000503:physiopathology*; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004847:Epithelial Cells / Q000382:microbiology; D005656:Fungal Proteins / Q000235:genetics / Q000378:metabolism*; D015966:Gene Expression Regulation, Fungal; D006801:Humans; D018613:Microscopy, Confocal; D046529:Microscopy, Electron, Transmission; D009061:Mouth Mucosa / Q000166:cytology / Q000382:microbiology*
chemical_list: D015820:Cadherins; D004268:DNA-Binding Proteins; D005656:Fungal Proteins; C489602:RIM101 protein, Candida albicans; D016282:Aspartic Acid Endopeptidases; C090755:SAP5 protein, Candida albicans