Roles for desmsomes in mRNA localization and translational regulation

Abstract Desmosomes are cell adhesion structures that provide mechanical stability to the epidermis and other tissues. Their canonical function is to link cells to the underlying intermediate filament network, and disruption of these linkages can lead to diverse pathologies including skin blistering and cardiomyopathies/dysplasias. For example, in autoimmune diseases collectively known as pemphigus, pathogenic antibodies targeting the desmosomes result in life-threatening blistering and loss of barrier function. We have identified a novel role for desmosomes in organizing the localization of mRNAs in the cell, as well as the localization of translational machinery and regulators. Further, perturbing desmosomes through wounding or through treatment with pathogenic pemphigus antibody disrupts the desmosome-dependent localization of translational regulators to the cell cortex. Based on these data, we propose that desmosomes are major regulators of mRNA and translational pathways. Additionally, we hypothesize that desmosomes are sensors of tissue integrity that alter translation in response to defective adhesion. Here we will determine the molecular mechanisms underlying cortical recruitment of mRNAs and translational regulators. Further, to define the functional relevance of translational control by desmosomes, we will determine the acute translational response upon desmosome disruption during both wounding and pemphigus. 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.