Regulation of intestinal epithelial intercellular adhesion and barrier function by desmosomal cadherin desmocollin-2

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.

Desmoplakin Maintains Transcellular Keratin Scaffolding and Protects From Intestinal Injury

“…11 Although the biological role of K8/K18 variants in inflammatory bowel disease remains to be clarified, 12 altered desmosomal protein levels are seen in individuals with inflammatory bowel disease and these changes may contribute to the impaired intestinal barrier seen in Crohn's disease. [13][14][15] These data are supported by findings in multiple transgenic models. Among them, K8 knockout mice show spontaneous colitis, 16 while loss of Dsg2, the only Dsg produced in intestinal epithelial cells, is well tolerated under basal conditions, but leads to increased susceptibility to both chemical and microbial injury.…”

“…Similar findings were made after the loss of desmosomal components Dsc2 and Dsg2, which lead to impaired intestinal adhesion. 14,15 The increased epithelial shedding into the intestinal lumen that was observed in DSP DIEC mice is compatible with the animals with intestinespecific plectin deletion that show increased cellular turnover and a trend toward higher epithelial detachment. 18 The fact that Dsp is crucial for cellular adhesion was supported further by our in vitro studies highlighting a higher cell mechanical fragility of Dsp-deficient cells.…”

The Influence of Nutrition on Intestinal Permeability and the Microbiome in Health and Disease

“…The regulation of IEB permeability is a complex, not clearly understood system. Intercellular junctions, such as tight junction, adherent junction, and desmosomes, have a key role in the paracellular passage ( 17 , 18 ). The subunits of these subcellular structures are located on the lateral membranes of the epithelial cells.…”

Mechanisms Causing Acantholysis in Pemphigus-Lessons from Human Skin

“…Finally, alterations in desmosome ultrastructure have been detected in patients suffering from inflammatory bowel disease (77,78). Because animal models deficient for Dsg2, Dsc2, and Dp have been shown to have intestinal epithelial barrier defects and disturbed wound healing and are prone to colitis (79)(80)(81)(82), several lines of evidence indicate that disturbed desmosomal adhesion contributes to the pathogenesis of inflammatory bowel diseases (83). In this respect, a new function of desmosomes has been elucidated as they control tight junction structure and function (84,85).…”