Zyxin and actin structure confer anisotropic YAP mechanotransduction

Tissues and the embedded cells experience anisotropic deformations due to their functions and anatomical locations. The resident cells, such as tenocytes and muscle cells, are often restricted by their extracellular matrix and organize parallel to their major loading direction, yet most studies on cellular responses to strains use isotropic substrates without predetermined organizations. To understand how confined cells sense and respond to anisotropic loading, we combine cell patterning and uniaxial stretch to have precise geometric control. Dynamic stretch parallel to the long axis of the cell activates YAP nuclear translocation, but not when stretched in the perpendicular direction. Looking at the initial cytoskeleton response, parallel stretch leads to actin breakage and repair within the first minute, mediated by zyxin, the focal adhesion protein. In addition, this zyxin-mediated repair response is controlled by focal adhesion kinase (FAK) and leads to YAP signaling. As these factors are intimately involved in a wide range of mechanical regulation, our findings point to new roles of zyxin and YAP in anisotropic mechanotransduction, and may provide additional perspectives in cellular adaptive responses and tissue homeostasis. STATEMENT OF SIGNIFICANCE: Structure and deformation of tissues control gene expression, migration, and proliferation of the resident cells. In an effort to understand the underlying mechanisms, we find that the transcription cofactor YAP respond to mechanical stretch in a direction-dependent manner. We demonstrate that parallel stretch induces actin cytoskeleton damage, focal adhesion kinase (FAK) activation, and zyxin relocation, which are involved in the anisotropic YAP signaling. Our findings provide additional perspectives in the interactions of tissue structure and cell mechanotransduction.