Desmogleins as signaling hubs regulating cell cohesion and tissue/organ function in skin and heart - EFEM lecture 2018.

Cell-cell contacts are crucial for intercellular cohesion and formation of endothelial and epithelial barriers. Desmosomes are the adhesive contacts providing mechanical strength to epithelial intercellular adhesion and therefore are most abundant in tissues subjected to high mechanical stress such as the epidermis and heart muscle. Desmogleins (Dsg) besides intercellular adhesion serve as signalling hubs regulating cell behaviour. In desmosomal diseases such as the autoimmune blistering skin disease pemphigus or arrhythmic cardiomyopathy (AC), which is caused by mutations of desmosomal components of cardiomyocyte intercalated discs, the adhesive and signalling functions of desmosomes are impaired. Therefore, our goal is to elucidate the mechanisms regulating adhesion of desmosomes in order to develop new strategies to treat desmosomal diseases. For pemphigus, we have provided evidence that intracellular signalling is required for loss of keratinocyte cohesion and have characterized a first disease-relevant adhesion receptor consisting of Dsg3 and p38MAPK. We propose that signalling patterns correlate with autoantibody profiles and thereby define the clinical phenotypes of pemphigus. Besides direct modulation of signalling pathways we have demonstrated that peptide-mediated crosslinking of Dsg molecules can abolish skin blistering in vivo. A similar approach may be effective to stabilize adhesion in cardiomyocytes of AC hearts. Since we observed that the adrenergic β1-receptor is localized at intercalated discs we evaluate signalling pathways regulating cardiomyocyte cohesion. With adrenergic signalling we have reported a first mechanism to stabilize desmosomal adhesion in intercalated discs and proposed a new function of the sympathicus in the heart we refer to as positive adhesiotropy.