Desmosomes compartmentalize mRNA and translation in the skin.

Subcellular compartmentalization allows cells to spatially control molecular functions. We show that in mouse and human epidermal cells, translational machinery is enriched at the cell cortex, where a large subset of mRNAs is also localized, defining a previously unrecognized axis of mRNA organization. The desmosomal protein desmoplakin is required for the cortical recruitment of both ribosomes and mRNAs via distinct mechanisms. Surprisingly, many cortex-localized transcripts are not actively translated but instead are translationally repressed. This spatially restricted regulation involves the RNA-induced silencing complex (RISC), which is also enriched at the cortex in a desmoplakin-dependent manner. Under homeostatic conditions, cortical RISC associates with mRNAs encoding cell adhesion and cytoskeletal proteins. Following wounding, these RISC-associated transcripts become translationally activated. Together, our findings reveal a dynamic, desmosome-dependent cortical compartmentalization of translation that responds to epithelial barrier disruption.