Abstract
Desmosomes provide intercellular adhesive strength required for integrity of epithelial and some non-epithelial tissues. Within the epidermis, the cadherin-type adhesion molecules desmoglein (Dsg) 1–4 and desmocollin (Dsc) 1–3 build the adhesive core of desmosomes. In keratinocytes, several isoforms of these proteins are co-expressed. However, the contribution of specific isoforms to overall cell cohesion is unclear. Therefore, in this study we investigated the roles of Dsg2 and Dsg3, the latter of which is known to be essential for keratinocyte adhesion based on its autoantibody-induced loss of function in the autoimmune blistering skin disease pemphigus vulgaris (PV). The pathogenic PV antibody AK23, targeting the Dsg3 adhesive domain, led to profound loss of cell cohesion in human keratinocytes as revealed by the dispase-based dissociation assays. In contrast, an antibody against Dsg2 had no effect on cell cohesion although the Dsg2 antibody was demonstrated to interfere with Dsg2 transinteraction by single molecule atomic force microscopy and was effective to reduce cell cohesion in intestinal epithelial Caco-2 cells which express Dsg2 as the only Dsg isoform. To substantiate these findings, siRNA-mediated silencing of Dsg2 or Dsg3 was performed in keratinocytes. In contrast to Dsg3-depleted cells, Dsg2 knockdown reduced cell cohesion only under conditions of increased shear. These experiments indicate that specific desmosomal cadherins contribute differently to keratinocyte cohesion and that Dsg2 compared to Dsg3 is less important in this context.
Highlights
Desmosomes facilitate intercellular adhesive strength in epithelial and some non-epithelial tissues
We provide evidence that Dsg2, when compared to Dsg3, is less important for cell-cell adhesion but is required for keratinocyte cohesion under conditions of increased mechanical stress indicating that the contribution of specific desmosomal cadherin isoforms to overall adhesive strength and tissue integrity is different
We compared the roles of the two desmosomal cadherins Dsg2 and Dsg3 for keratinocyte cohesion, the latter of which is well established to be important for epidermal integrity from its involvement in the pathogenesis of pemphigus vulgaris (PV) [5], in a human cell culture model
Summary
Desmosomes facilitate intercellular adhesive strength in epithelial and some non-epithelial tissues. Cell cohesion is provided by transinteraction of the extracellular N-terminal domain of specific desmosomal cadherin isoforms from adjacent cells. Dsg has been identified as one of the autoantigens in the autoimmune blistering skin disease pemphigus vulgaris (PV) [5] In this disease, circulating autoantibodies targeting Dsg and Dsg induce loss of cell cohesion (termed acantholysis) within the epidermis and mucous membranes. A novel role for Dsg as a binding partner for caveolin-1 has been reported [10] Via this interaction Dsg might be involved in desmosome turnover and intracellular signaling events. We provide evidence that Dsg, when compared to Dsg, is less important for cell-cell adhesion but is required for keratinocyte cohesion under conditions of increased mechanical stress indicating that the contribution of specific desmosomal cadherin isoforms to overall adhesive strength and tissue integrity is different
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