MECHANISMS OF DESMOSOME REGULATION IN SKIN DISEASE

桥粒是细胞间的粘连连接，在表皮中起着关键作用。 通过调节强大的细胞-细胞黏附和调节信号通路来实现动态平衡 调节表皮分化。桥粒的重要性被大量的 自身免疫性和遗传性皮肤病，损害桥粒功能并导致表皮 脆弱。这些疾病包括寻常型天疱疮(PV)，一种严重的自身免疫性表皮水泡 针对桥粒钙粘蛋白桥粒粘附素-3的自身抗体(IgG)引起的疾病 (Dsg3)，以及由以下原因引起的严重皮炎、多重过敏和代谢衰竭(SAM)综合征 DSG1功能缺失突变。我们之前对PV的研究表明，桥粒蛋白是 与脂筏有关，我们最近的发现表明，Dsg1TMD的一个突变 废除脂筏联系，影响桥粒形成，并导致SAM综合征。 脂筏对于多种细胞功能是重要的，包括信号、内吞和 膜结构域形成。脂筏在不同类型糖尿病患者DSG功能调节中的作用 皮肤病强调DSG与正常桥粒中的脂筏相关的重要性 功能和表皮动态平衡。我们假设DSG需要与筏子相关联 桥粒组装，从粘连连接分离，以及用于DSG粘合剂和信号 维持表皮动态平衡所必需的活动。这项提案中概述的实验包括 旨在揭示桥粒钙粘附素的RAFT靶向特性，RAFT如何与 调节桥粒和黏附连接膜结构域的形成，以及DSG如何丢失 关联导致SAM综合征。这些研究的结果将从根本上产生新的 桥粒调控的概念性模型，将构成皮肤治疗的基础 与桥粒功能丧失相关的疾病。

Desmosomes are adhesive intercellular junctions that play critical roles in epidermal homeostasis by mediating robust cell-cell adhesion and by modulating signaling pathways that regulate epidermal differentiation. The importance of desmosomes is highlighted by numerous autoimmune and inherited skin diseases that compromise desmosome function and cause epidermal fragility. These diseases include pemphigus vulgaris (PV), a severe autoimmune epidermal blistering disease caused by autoantibodies (IgG) directed against the desmosomal cadherin desmoglein-3 (Dsg3), and severe dermatitis, multiple allergies and metabolic wasting (SAM) syndrome caused by DSG1 loss of function mutations. Our previous studies of PV revealed that desmosomal proteins are associated with lipid rafts, and our recent findings indicate that a mutation in the Dsg1TMD that abrogates lipid raft association, compromises desmosome formation, and causes SAM syndrome. Lipid rafts are important for a variety of cellular functions, including signaling, endocytosis and membrane domain formation. The important role of lipid rafts in regulating Dsg function in different skin diseases underscores the importance of Dsg association with lipid rafts in normal desmosome function and epidermal homeostasis. We hypothesize that Dsg association with rafts is required for desmosome assembly, segregation from adherens junctions, and for Dsg adhesive and signaling activities necessary for epidermal homeostasis. The experiments outlined in this proposal are designed to reveal the raft targeting features of desmosomal cadherins, how raft association regulates desmosome and adherens junction membrane domain formation, and how loss of Dsg raft association leads to SAM syndrome. The outcome of these studies will produce fundamentally new conceptual models for desmosome regulation and will form a foundation for the treatment of skin diseases associated with loss of desmosome function.