Translational Regulation by Desmosomes

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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.