BPS2026 – Mechanochemical simulations predict changes in YAP/TAZ nuclear localization as a function of nuclear envelope stretch

Cell mechanotransduction relies on transduction of stress from the plasma membrane to the nuclear envelope, mediated by interactions between cytoskeletal (e.g., actin) and nucleoskeletal (e.g., lamin A/C) components. For instance, studies have shown that compression of the nucleus leads to enhanced nuclear transport of transcription regulatory factors such as YAP and TAZ. Cells migrating through 3D matrices or spreading on substrates with nanotopography show complex nuclear deformations that lead to nuclear envelope stretch and rupture. Here, we use biophysical simulations to systematically examine the interplay between nuclear deformation and changes to YAP/TAZ mechanotransduction on substrates with nanotopography. We model the nuclear envelope as a hyperelastic shell with finite thickness and solve for its deformations on substrates with cylindrical nanopillars using the finite element method. We introduce a time-dependent downward force on the upper region of the nucleus to model the effects of the perinuclear actin cap. Our simulations show that there are regions of enhanced nuclear envelope stretch and lamin accumulation at the inner nuclear surface directly adjacent to the outer edge of the nanopillars. When integrated with a model of YAP/TAZ mechanotransduction, our simulations predict that these deformations lead to enhanced YAP/TAZ nuclear localization as a function of nuclear compression. We then consider the occurrence of nuclear envelope rupture at regions with lower lamin density. Assuming a single rupture event allows for rapid transport across one region of lamin depletion, our model recapitulates the changes in YAP or Ku-80 localization observed following rupture in U2OS cells. Altogether, our mechanochemical model suggests that the time-dependent reorganization of nuclear lamins can serve as a mechanism regulating nuclear envelope stretch and the likelihood of nuclear rupture.