Description:
The desmosomal transmembrane adhesion molecule desmoglein 3 (Dsg3) is required for strong keratinocyte cohesion. Recently, we have shown that Dsg3 loss of function, either by siRNA silencing or by peptides interfering with Dsg3 binding, increases the activity of p38MAPK. In this study, we aim to investigate the physiological role of Dsg3‐dependent p38MAPK suppression. Dsg3‐deficient mice display repetitive skin erosions most of which rapidly heal spontaneously. In lysates from wound biopsies but also from perilesional areas, p38MAPK activation was detectable compared to control animals. Similarly, in skin biopsies of pemphigus patients which suffer from impaired cell cohesion due to autoantibodies targeting Dsg3, p38MAPK activity was increased in areas of epidermal blistering. This led us to speculate that Dsg3 regulates wound repair in a p38MAPK‐dependent manner. Indeed, silencing of Dsg3 resulted in increased p38MAPK activity which was paralleled by enhanced migration speed. In line with this, scratch wounded keratinocyte monolayers exhibited p38MAPK activation in cells lining the wound edge. Importantly, migration was efficiently blocked by inhibition of p38MAPK both in control and Dsg3 knockdown keratinocytes. These data indicate that Dsg3 via p38MAPK inhibition prevents a switch from an adhesive to a migratory keratinocyte phenotype. Upon wounding, impaired Dsg3 adhesion may thus favor wound closure by facilitating p38MAPK‐dependent migration.