Regulation of intestinal epithelial intercellular adhesion and barrier function by desmosomal cadherin desmocollin-2
Open Access
- 15 April 2021
- journal article
- research article
- Published by American Society for Cell Biology (ASCB) in Molecular Biology of the Cell
- Vol. 32 (8), 753-768
- https://doi.org/10.1091/mbc.e20-12-0775
Abstract
The role of desmosomal cadherin desmocollin-2 (Dsc2) in regulating barrier function in intestinal epithelial cells (IECs) is not well understood. Here, we report the consequences of silencing Dsc2 on IEC barrier function in vivo using mice with inducible intestinal-epithelial specific Dsc2 knockdown (Dsc2ERΔIEC). While the small intestinal gross architecture was maintained, loss of epithelial Dsc2 influenced desmosomal plaque structure, which was smaller in size and had increased intermembrane space between adjacent epithelial cells. Functional analysis revealed that loss of Dsc2 increased intestinal permeability in vivo, supporting a role for Dsc2 in the regulation of intestinal epithelial barrier function. These results were corroborated in model human IECs in which Dsc2 knockdown resulted in decreased cell-cell adhesion and impaired barrier function. It is noteworthy that Dsc2 knockdown cells exhibited delayed recruitment of desmoglein-2 (Dsg2) to the plasma membrane after calcium switch-induced intercellular junction reassembly, while E-cadherin accumulation was unaffected. Mechanistically, loss of Dsc2 increased desmoplakin (DP I/II) protein expression and promoted intermediate filament interaction with DP I/II, and was associated with enhanced tension on desmosomes as measured by a Dsg2-tension sensor. In conclusion, we provide new insights on Dsc2 regulation of mechanical tension, adhesion and barrier function in intestinal epithelial cells.Keywords
This publication has 74 references indexed in Scilit:
- JAM-A associates with ZO-2, afadin, and PDZ-GEF1 to activate Rap2c and regulate epithelial barrier functionMolecular Biology of the Cell, 2013
- E-cadherin is under constitutive actomyosin-generated tension that is increased at cell–cell contacts upon externally applied stretchProceedings of the National Academy of Sciences of the United States of America, 2012
- Characterization of full-length and proteolytic cleavage fragments of desmoglein-2 in native human colon and colonic epithelial cell linesCell Adhesion & Migration, 2011
- Loss of desmocollin-2 confers a tumorigenic phenotype to colonic epithelial cells through activation of Akt/β-catenin signalingMolecular Biology of the Cell, 2011
- Membrane-impermeable Cross-linking Provides Evidence for Homophilic, Isoform-specific Binding of Desmosomal Cadherins in Epithelial CellsOnline Journal of Public Health Informatics, 2011
- Measuring mechanical tension across vinculin reveals regulation of focal adhesion dynamicsNature, 2010
- Intercellular Junction Assembly, Dynamics, and HomeostasisCold Spring Harbor Perspectives in Biology, 2009
- The Intermediate Filament Network in Cultured Human Keratinocytes Is Remarkably Extensible and ResilientPLOS ONE, 2008
- JAM-A regulates permeability and inflammation in the intestine in vivoThe Journal of Experimental Medicine, 2007
- Desmoglein-2: A Novel Regulator of Apoptosis in the Intestinal EpitheliumMolecular Biology of the Cell, 2007