Translational Regulation by Desmosomes

摘要 桥粒是细胞-细胞粘附结构，其对于细胞的机械强度是必不可少的。 表皮和心脏。桥粒的破坏会导致破坏性的水泡性疾病， 皮肤和心肌病/发育不良。而桥粒的典型作用是提供 机械弹性通过绑定中间丝细胞骨架，出现非- 典型的功能表明桥粒是组织许多方面的重要整合者 physiology.我们的长期目标是了解表皮中桥粒的功能 并确定细胞如何响应于细胞中产生的致病性抗桥粒抗体， 自身免疫性疾病天疱疮我们有了令人兴奋的发现桥粒 翻译调节子传递到细胞皮层。我们假设桥粒是组织的传感器 完整性改变翻译以响应有缺陷的粘附。定义功能相关性 翻译控制桥粒，我们将确定翻译反应后，急性 使用致病性天疱疮抗体破坏桥粒。此外，我们将使用单一 分子实时成像方法来确定蛋白质翻译的网站下， 稳态条件和当桥粒被破坏时。这项工作将定义小说 细胞粘附调节转录后基因表达的机制，这可能有 在感知和响应上皮完整性缺陷中的基本功能。

Abstract Desmosomes are cell-cell adhesion structures that are essential for the mechanical strength of the epidermis and heart. Disruption of desmosomes results in devastating blistering diseases of the skin and in cardiomyopathies/dysplasias. While the canonical role of desmosomes is to provide mechanical resilience through binding the intermediate filament cytoskeleton, emerging non- canonical functions suggest that desmosomes are important integrators of many aspects of tissue physiology. Our long-term goals are to understand the functions of desmosomes in the epidermis and to determine how cells respond to pathogenic anti-desmosomal antibodies produced in the autoimmune diseases, pemphigus. We have made the exciting discovery that desmosomes recruit translational regulators to the cell cortex. We hypothesize that desmosomes are sensors of tissue integrity that alter translation in response to defective adhesion. To define the functional relevance of translational control by desmosomes, we will determine the translational response upon acute disruption of desmosomes using pathogenic pemphigus antibodies. In addition, we will use single molecule live-imaging approaches to determine the sites of protein translation under both homeostatic conditions and when desmosomes are disrupted. This work will define novel mechanisms for cell adhesions in regulating post-transcriptional gene expression, which may have essential functions in sensing and responding to defects in epithelial integrity.