Desmosomes Regulate Translation and mRNA at the Cell Cortex

Abstract

Desmosomes, traditionally known for their role in cell adhesion, are emerging as multifunctional hubs that influence signaling, cytoskeletal organization, and localized translation. This study uncovers novel functions of desmosomes in keratinocytes, demonstrating their involvement in the localization and regulation of mRNAs and translation. Through proximity-based proteomics, transcriptomics, and translatomics, desmosomes are shown to localize translation machinery and specific mRNAs to the cell cortex in a desmoplakin-dependent manner. Despite their localization, many enriched mRNAs remain untranslated, suggesting a repressive mechanism involving the RNA-induced silencing complex (RISC). Following mechanical perturbation through scratch wounding, keratinocytes exhibit rapid changes in the translation of adhesion and cytoskeletal proteins, while total mRNA levels remain unchanged. These findings support a model of post-transcriptional control mediated by mRNA localization, the RISC complex, and other mRNA-regulating proteins. Furthermore, this work introduces a four-tiered approach integrating BioID, RNA sequencing, polysome profiling, and Clear-CLIP to study compartmentalized translation. The implications extend beyond keratinocytes, as desmosome-associated translation may play critical roles in mechanically active tissues like the heart. This study broadens our understanding of desmosomes as dynamic organizers of localized translation and potential regulators of stress response and disease.