Lamin A redistribution mediated by nuclear deformation determines dynamic localization of YAP

Abstract

YAP is a key mechanotransduction protein with essential roles in diverse physiological processes. Dysregulation in YAP activity is associated with multiple diseases such as atherosclerosis, fibrosis, and cancer progression. Here we examine the physical stimuli that regulate dynamic YAP translocation to the nucleus. Through a combination of biophysical studies, we demonstrate that YAP localization is insensitive to cell substrate stiffness, but strongly determined by cellular contractile work, which in turn deforms the nucleus. We show that nuclear deformation from LINC-mediated cytoskeletal contractility or extracellular osmotic forces triggers YAP nuclear localization. By modulating the expression of lamin A and nuclear stiffness, we illustrate that nuclear rigidity modulates deformation-mediated YAP nuclear localization. Finally, we show that nuclear deformation causes relocalization of lamin A from the nuclear membrane to the nucleoplasm, and this is essential in allowing YAP to enter the nucleus. These results reveal key physical nuclear deformation mechanics that drive YAP nuclear import.