Leal-Fischer, K.; Franz, H.; Buczak, K.; Zimmermann, A.; Spindler, V.

Background: Skin is constantly exposed to mechanical forces such as pressure and friction, which need to be sensed and buffered to ensure tissue homeostasis and barrier function. Desmosomes are essential for epidermal integrity, but their role in converting mechanical cues into cellular signaling responses are not well understood. Methods: Here, we combine proteomics and shear-stress assays with live-cell reporters to investigate how desmosomes modulate stress-kinase pathways in keratinocytes. Results: We show that the desmosomal adhesion molecule DSG3 is essential not only for cell-cell adhesion but also for modulating p38MAPK and ERK signaling. Loss of DSG3 disrupts mechanotransduction-related protein networks, including the expression of the mechanosensitive channel Piezo1. Under static conditions, DSG3 dampens ERK activity via Piezo1-dependent mechanisms, whereas DSG3 suppresses p38MAPK activity through an independent mechanism. In contrast, DSG3 is required to trigger an activation of both ERK and p38MAPK in response to shear stress in a Piezo1-dependent manner. Experiments with domain-specific DSG3 mutants demonstrate that cell cohesion and signaling responses are partially uncoupled, while maintaining DSG3 tail integrity was crucial for p38MAPK and ERK responses. Conclusion: These findings demonstrate that DSG3 independently coordinates adhesion and mechanotransduction in a domain-specific manner, providing novel insights into how DSG3 contributes to epithelial integrity under dynamic mechanical environments.