Regulation of desmosomal hyperadhesion in epidermal barrier function and tissue integrity

桥粒是细胞间的黏附结构，对表皮组织的完整性至关重要。它们的成分属于多基因家族，从而产生可变组成的桥粒。到目前为止，上下文依赖性成分在表皮分化过程中桥粒形成、动力学或稳定性中的功能意义尚不完全清楚。桥粒可以出现两种功能上截然不同的粘附状态，这两种状态的区别在于它们对钙缺乏的反应：在正常组织中，桥粒采用不依赖钙的状态，也称为高粘附。相反，在再生和伤口愈合过程中，桥粒体粘连变得依赖钙，导致细胞间凝聚力减弱，从而导致组织重塑。到目前为止，人们对单个桥粒体蛋白对高粘连的不同作用知之甚少。我们最近的研究表明，亲血小板蛋白1和3是桥粒斑块的组成部分，在表皮中具有不同的表达模式，它们对稳定的细胞间粘附的贡献根本不同：然而亲血小板蛋白1是高粘附所必需的，因此稳定的亲血小板蛋白3赋予了与可塑性相容的动态状态。此外，我们已经证明嗜血小板蛋白1在桥粒中的定位和功能是通过IGF-1/胰岛素信号磷酸化调节的。目前的建议的目的是阐明导致高粘连的机制，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，我们将分析桥粒的组成是如何对超粘连状态和动态状态做出贡献的，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以及PKCalpha如何调节桥粒蛋白相互作用或定位的确切机制都没有被研究过。此外，桥粒蛋白包括桥粒钙粘蛋白和亲血小板蛋白被棕榈酰化。同样，这种修饰在桥粒体动力学和稳定性中的作用以及相关的酶都没有被研究过。最后，我们将描述高黏附与动态桥粒在表皮屏障功能和组织完整性方面的生理作用。我们希望我们的研究能为表皮分化和再生过程中桥粒依赖性粘附和屏障功能的调控提供新的见解。此外，鉴定那些对高粘连及其调控至关重要的桥粒体蛋白将使我们能够解决高粘连是否以及如何保护组织免受机械和其他压力导致的特应性皮炎、牛皮癣或自身免疫性疾病寻常性天疱疮的损伤的问题。

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.