Abstract
Desmosomes are essential cell-cell adhesion organelles that enable tension-prone tissues, like the skin and heart, to withstand mechanical stress. Desmosomal anomalies are associated with numerous epidermal disorders, cardiomyopathies, and cancer. Despite their critical importance, how desmosomes sense and respond to mechanical stimuli is not understood. Here, we combine super-resolution imaging in epithelial cells and primary cardiomyocytes, FRET-based tension sensors, atomistic computer simulations, and biochemical assays to demonstrate that actomyosin forces induce a conformational change in desmoplakin, a key cytoplasmic desmosomal protein. We show that in human breast cancer MCF7 cells, keratin-19 couples F-actin filaments to desmosomes and regulates the level of actomyosin forces integrated into the desmosomal complex. We demonstrate that actomyosin contractility reorients keratin intermediate filaments and directs force to desmoplakin along the keratin network, plausibly converting the N-terminal plakin domain from a folded to an extended conformation. We also show that desmoplakin undergoes a similar actomyosin force-dependent conformational change in primary cardiomyocytes, with the extent of the change affected by myofibril orientation. Our findings establish that desmoplakin is mechanosensitive and its structural states reflect the level of forces transmitted through the actin network across cell types.