EpCAM proteolysis and release of complexed claudin-7 repair and maintain the tight junction barrier

TJs maintain the epithelial barrier by regulating paracellular permeability. Since TJs are under dynamically fluctuating intercellular tension, cells must continuously survey and repair any damage. However, the underlying mechanisms allowing cells to sense TJ damage and repair the barrier are not ye...

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Published inThe Journal of cell biology Vol. 222; no. 1; p. 1
Main Authors Higashi, Tomohito, Saito, Akira C., Fukazawa, Yugo, Furuse, Mikio, Higashi, Atsuko Y., Ono, Masahiro, Chiba, Hideki
Format Journal Article
LanguageEnglish
Published United States Rockefeller University Press 02.01.2023
Subjects
Adhesion
Biochemistry
Cell Signaling
Cell size
Claudins - genetics
Claudins - metabolism
Damage
Epithelial Cell Adhesion Molecule - genetics
Epithelial Cell Adhesion Molecule - metabolism
Gene Knockout Techniques
Maintenance
Mannose-Binding Protein-Associated Serine Proteases - metabolism
Mannose-binding protein-associated serine proteinase
Membranes
Permeability
Physiology
Proteolysis
Repair
Serine proteinase
Tight Junctions - metabolism
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ISSN0021-9525
1540-8140
1540-8140
DOI10.1083/jcb.202204079

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Summary:TJs maintain the epithelial barrier by regulating paracellular permeability. Since TJs are under dynamically fluctuating intercellular tension, cells must continuously survey and repair any damage. However, the underlying mechanisms allowing cells to sense TJ damage and repair the barrier are not yet fully understood. Here, we showed that proteinases play an important role in the maintenance of the epithelial barrier. At TJ break sites, EpCAM–claudin-7 complexes on the basolateral membrane become accessible to apical membrane-anchored serine proteinases (MASPs) and the MASPs cleave EpCAM. Biochemical data and imaging analysis suggest that claudin-7 released from EpCAM contributes to the rapid repair of damaged TJs. Knockout (KO) of MASPs drastically reduced barrier function and live-imaging of TJ permeability showed that MASPs-KO cells exhibited increased size, duration, and frequency of leaks. Together, our results reveal a novel mechanism of TJ maintenance through the localized proteolysis of EpCAM at TJ leaks, and provide a better understanding of the dynamic regulation of epithelial permeability.
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ISSN:0021-9525
1540-8140
1540-8140
DOI:10.1083/jcb.202204079