Nanoscale Curvature Regulates YAP/TAZ Nuclear Localization Through Nuclear Deformation and Rupture

Area of Science:

• Biophysics
• Cell Biology
• Mechanobiology

Background:

• Nuclear translocation of YAP/TAZ proteins is a key indicator of cellular mechanotransduction.
• Cells exhibit mechanoadaptation to nanotopographical substrates, involving integrin endocytosis, actin dynamics, and nuclear deformation.

Purpose of the Study:

• To investigate how cells integrate responses to local nanotopographical cues across multiple length scales.
• To develop a biophysical model explaining cellular mechanoadaptation to nanopillar substrates.

Main Methods:

• A biophysical model incorporating plasma membrane curvature-dependent endocytosis and actin assembly.
• Modeling stretch-induced opening of nuclear pore complexes in the nuclear envelope.
• Utilizing cell shapes from electron micrographs and fluorescence images for model validation.

Main Results:

• The model recapitulates reduced global cytoskeletal assembly on nanopillars, compensated by local actin assembly and nuclear indentation.
• Enhanced YAP/TAZ transport through stretched nuclear pore complexes is predicted.
• Simulations predicted and experiments validated nuclear YAP/TAZ accumulation following nuclear envelope rupture.

Conclusions:

• Nanotopography modulates mechanotransduction through integrated cellular responses.
• Positive and negative feedback mechanisms on mechanotransduction are tuned by nanotopography.
• Cellular adaptation to nanotopography involves complex interplay between local and global cellular mechanics.