title: The epithelium in inflammatory bowel disease: potential role of endocytosis of junctional proteins in barrier disruption.
abstract: A key feature of inflammatory bowel disease (IBD) is disruption of the intestinal epithelial barrier by unknown mechanisms. Integrity of the epithelial barrier is determined by an apical junctional complex that is composed of tight junction (TJ) and adherens junction (AJ). Previous observations have suggested that alterations in the apical junctional complex occur in IBD. Localization studies in mucosal biopsies from IBD patients have revealed disappearance of key TJ (occludin, JAM1, ZO1, claudin 1) and AJ (E-cadherin, beta-catenin) proteins from intercellular junctions. In vitro experiments examining the effects of inflammatory cytokines on model intestinal epithelial monolayers suggest that disruption of the epithelial barrier is associated with internalization of transmembrane TJ proteins, JAM1, ocdudin and claudins 1/4. The mechanism(s) of internalization of intercellular junctions can be modelled in vitro by calcium depletion of confluent epithelial cell monolayers. Using this model, we have observed rapid, orchestrated endocytosis of all AJ and TJ proteins into a subapical cytoplasmic compartment that is independent of caveolae/lipid rafts and macropinocytosis. However, inhibitors of clathrin-mediated endocytosis effectively block internalization of AJs and TJs, and junctional proteins colocalize with clathrin. Interestingly, internalized AJ and TJ proteins enter early endosomes followed by movement to organelles that do not label with markers of late and recycling endosomes, lysosomes or Golgi but appear to represent a unique storage compartment that colocalizes with t-SNARE protein, syntaxin 4. A better understanding of the mechanisms of junctional internalization and recycling will likely provide new insights into the mechanisms of altered barrier function in IBD.
authors.affiliation: Epithelial Pathobiology Research Unit, Department of Pathology and Laboratory Medicine, Whitehead Research Building, Emory University, 615 Michael Street, Atlanta, GA 30322, USA.
authors.forename: Andrei I
authors.initials: AI
authors.lastname: Ivanov
authors.forename: Asma
authors.initials: A
authors.lastname: Nusrat
authors.forename: Charles A
authors.initials: CA
authors.lastname: Parkos
mesh_terms: D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D004705:Endocytosis; D004847:Epithelial Cells / Q000473:pathology*; D004848:Epithelium / Q000473:pathology*; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000473:pathology*; D007422:Intestines / Q000166:cytology; D021962:Membrane Microdomains / Q000737:chemistry; D046912:Multiprotein Complexes / Q000378:metabolism; D019108:Tight Junctions; D013997:Time Factors
chemical_list: D046912:Multiprotein Complexes; D002118:Calcium