Nanoscale curvature of the plasma membrane regulates mechanoadaptation through nuclear deformation and rupture

Nuclear translocation of the transcription regulatory proteins YAP and TAZ is a critical readout of cellular mechanotransduction. Recent experiments have demonstrated that cells on substrates with well-defined nanotopographies exhibit an altered mechanical and signaling response when compared to those on flat substrates, demonstrating mechanoadaptation to geometric constraints. Specifically, such cells show lower rates of focal adhesion formation, resulting in lower amounts of YAP/TAZ nuclear translocation. In this study, we investigate how the crosstalk between substrate nanotopography and mechanotransduction affects cytoskeletal activity and the nuclear transport of YAP/TAZ. We develop a biophysical model that incorporates plasma membrane (PM) curvature-dependent inhibition of integrin-mediated signaling, PM curvature-sensitive actin assembly, and stretch-induced opening of nuclear pore complexes (NPCs) upon indentation of the nuclear envelope (NE) by nanopillars. Our model predicts lower levels of cytoskeletal activation on nanopillar substrates, consistent with experiments. We demonstrate that this effect can be partially compensated for by increasing the indentation of the NE, leading to local cytoskeletal accumulation and enhanced YAP/TAZ transport through stretched NPCs. Nuclear deformation and cytoskeletal arrangement in our model agree well with experimental fluorescence images and electron micrographs of cells on nanopillar substrates. We then use our model to predict the effects of NE rupture on YAP/TAZ nuclear abundance, showing that if nuclear entry is favored over export through these rupture-induced pores, YAP/TAZ accumulates in the nucleus. We confirm this prediction experimentally, showing that nuclear YAP/TAZ increases in cells with ruptured NEs.