Regulation of desmosomal hyperadhesion in epidermal barrier function and tissue integrity

桥粒是表皮组织完整性所必需的细胞-细胞粘附结构。它们的成分属于多基因家族，产生可变组成的桥粒。到目前为止，上下文依赖的组合物在表皮分化过程中桥粒形成、动力学或稳定性的功能意义还不完全清楚。桥粒可以以两种功能不同的粘附状态出现，其特征在于它们对钙耗尽的反应：在正常组织中，桥粒采取钙非依赖性状态，也称为过度粘附。相反，在再生和伤口愈合过程中，桥粒粘附变得依赖于钙，导致细胞间凝聚力较弱，从而允许组织重塑。到目前为止，很少有人知道个别桥粒蛋白的差异贡献超粘附。我们最近发现，plakophilin 1和3，在表皮中具有不同表达模式的桥粒斑块的组成部分，在其对稳定的细胞间粘附的贡献方面有根本性的不同：而plakophilin 1是过度粘附所需的，因此稳定性plakophilin 3赋予了一个与可塑性相容的动态状态。此外，我们已经证明，plakophilin 1在桥粒中的定位和功能是通过其磷酸化通过IGF-1/insulin signaling.The目前的建议的目的是阐明导致过度粘附的机制，同时允许逆转，从而促进桥粒的重塑和可塑性。在这种程度上，我们将分析桥粒组合物如何有助于超粘附与动态状态，以及哪些分子机制调节这些状态及其相互转换。虽然研究结果表明PKCalpha在这一过程中的作用，但它在桥粒中的靶点和PKCalpha如何调节桥粒蛋白相互作用或定位的精确机制都没有被研究。此外，桥粒蛋白质包括桥粒钙粘蛋白和斑嗜蛋白变成棕榈酰化。同样，这种修饰在桥粒动力学和稳定性中的功能以及相关的酶都没有被研究。最后，我们将描述超粘附与动态桥粒在表皮屏障功能和组织完整性中的生理作用，我们希望我们的研究为表皮分化和再生过程中桥粒依赖的粘附和屏障功能的调节提供新的见解。此外，这些桥粒蛋白的识别是必不可少的超粘附和他们的监管将使我们能够解决的问题，如果和如何超粘附可以保护组织损伤的机械和其他应力导致特应性皮炎，牛皮癣或自身免疫性疾病寻常天疱疮。

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.