Regulation of desmosomal hyperadhesion in epidermal barrier function and tissue integrity

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Desmosomes are cell-cell adhesive structures essential for tissue integrity of the epidermis. Their constituents belong to multigene families giving rise to desmosomes of variable composition. So far, the functional significance of context-dependent composition in desmosome formation, dynamics or stability during epidermal differentiation is incompletely understood. Desmosomes can occur in two functionally distinct adhesive states, which are distinguished by their reaction to calcium depletion: In normal tissues, desmosomes adopt a calcium-independent state, also referred to as hyperadhesion. In contrast, during regeneration and wound healing, desmosomal adhesion becomes calcium-dependent resulting in weaker intercellular cohesion that allows for tissue remodeling. So far little is known about the differential contribution of individual desmosomal proteins to hyperadhesion. We have recently shown that plakophilins 1 and 3, components of the desmosomal plaque with distinct expression patterns in the epidermis, differ fundamentally in their contribution to stable intercellular adhesion: Whereas plakophilin 1 was required for hyperadhesion and thus stability plakophilin 3 conferred a dynamic state compatible with plasticity. Moreover, we have demonstrated that the localization and function of plakophilin 1 in the desmosome is regulated by its phosphorylation via IGF-1/insulin signaling.The aim of the current proposal is to elucidate the mechanisms leading to hyperadhesion and at the same time allowing reversion thus facilitating remodeling and plasticity of desmosomes. To this extent we will analyze how desmosome composition contributes to a hyperadhesive versus a dynamic state and which molecular mechanisms regulate these states and their interconversion. Although findings suggest a role of PKCalpha in this process neither its targets in the desmosome nor the precise mechanism how PKCalpha modulates desmosomal protein interactions or localization have been studied. Moreover, desmosomal proteins including the desmosomal cadherins and plakophilins become palmitoylated. Again, neither the function of this modification in desmosomal dynamics and stability nor the relevant enzymes have been studied. Finally, we will characterize the physiological role of hyperadhesive versus dynamic desmosomes in epidermal barrier function and tissue integrity.We expect that our studies provide novel insight into the regulation of desmosome dependent adhesion and barrier function during epidermal differentiation and regeneration. Moreover, the identification of those desmosomal proteins that are essential for hyperadhesion and their regulation will enable us to address the question if and how hyperadhesion can protect from tissue damage by mechanical and other stresses leading to atopic dermatitis, psoriasis or the autoimmune disease Pemphigus vulgaris.