title: Matriptase-mediated cleavage of EpCAM destabilizes claudins and dysregulates intestinal epithelial homeostasis.
abstract: Congenital tufting enteropathy (CTE) is a severe autosomal recessive human diarrheal disorder with characteristic intestinal epithelial dysplasia. CTE can be caused by mutations in genes encoding EpCAM, a putative adhesion molecule, and HAI-2, a cell surface protease inhibitor. A similar phenotype occurs in mice whose intestinal epithelial cells (IECs) fail to express the tight junction-associated protein claudin-7. EpCAM stabilizes claudin-7 in IECs, and HAI-2 regulates the cell surface serine protease matriptase, a known modifier of intestinal epithelial physiology. Therefore, we hypothesized that HAI-2, matriptase, EpCAM, and claudin-7 were functionally linked. Herein we have demonstrated that active matriptase cleaves EpCAM after Arg80 and that loss of HAI-2 in IECs led to unrestrained matriptase activity and efficient cleavage of EpCAM. Cleavage of EpCAM decreased its ability to associate with claudin-7 and targeted it for internalization and lysosomal degradation in conjunction with claudin-7. CTE-associated HAI-2 mutant proteins exhibited reduced ability to inhibit matriptase and also failed to efficiently stabilize claudin-7 in IECs. These results identify EpCAM as a substrate of matriptase and link HAI-2, matriptase, EpCAM, and claudin-7 in a functionally important pathway that causes disease when it is dysregulated.
authors.forename: Chuan-Jin
authors.initials: CJ
authors.lastname: Wu
authors.forename: Xu
authors.initials: X
authors.lastname: Feng
authors.forename: Michael
authors.initials: M
authors.lastname: Lu
authors.forename: Sohshi
authors.initials: S
authors.lastname: Morimura
authors.forename: Mark C
authors.initials: MC
authors.lastname: Udey
mesh_terms: D000818:Animals; D018938:Caco-2 Cells; D057167:Claudins / Q000235:genetics / Q000378:metabolism*; D000071858:Epithelial Cell Adhesion Molecule / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D055550:Protein Stability; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism*
chemical_list: C473255:CLDN7 protein, human; D057167:Claudins; C507360:Cldn7 protein, mouse; C499379:EPCAM protein, human; D000071858:Epithelial Cell Adhesion Molecule; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; C109148:SPINT2 protein, human; C533525:Spint2 protein, mouse; D012697:Serine Endopeptidases; C485596:ST14 protein, human; C118992:St14 protein, mouse