Transfer function for YAP/TAZ nuclear translocation revealed through spatial systems modeling

Abstract

YAP/TAZ is a master regulator of mechanotransduction whose functions rely on translocation from the cytoplasm to the nucleus in response to diverse physical cues. Substrate stiffness, substrate dimensionality, and cell shape are all input signals for YAP/TAZ, and through this pathway, regulate critical cellular functions and tissue homeostasis. Yet, the relative contributions of each biophysical signal and the mechanisms by which they synergistically regulate YAP/TAZ in realistic tissue microenvironments that provide multiplexed input signals remains unclear. For example, in simple 2D culture, YAP/TAZ nuclear localization correlates strongly with substrate stiffness, while in 3D environments, YAP/TAZ translocation can increase with stiffness, decrease with stiffness, or remain unchanged. Here, we develop a spatial model of YAP/TAZ translocation to enable quantitative analysis of the relationships between substrate stiffness, substrate dimensionality, and cell shape. Our model couples cytosolic stiffness to nuclear mechanics to replicate existing experimental trends, and extends beyond current data to predict that increasing substrate activation area through changes in culture dimensionality, while conserving cell volume, forces distinct shape changes that result in nonlinear effect on YAP/TAZ nuclear localization. Moreover, differences in substrate activation area versus total membrane area can account for counterintuitive trends in YAP/TAZ nuclear localization in 3D culture. Based on this multiscale investigation of the different system features of YAP/TAZ nuclear translocation, we predict that how a cell reads its environment is a complex information transfer function of multiple mechanical and biochemical factors. These predictions reveal design principles of cellular and tissue engineering for YAP/TAZ mechanotransduction. STATEMENT OF SIGNIFICANCEIn chemical engineering, a transfer function is a mathematical function that models the output of a reactor for all possible inputs, and enables the reliable design and operation of complex reaction systems. Here, we apply this principle to cells to derive the transfer function by which substrate stiffness is converted into YAP/TAZ nuclear localization. This function is defined by a spatial model of the YAP/TAZ mechano-chemical sensing network, wherein key spatial and physical inputs to the system, namely cell and nuclear shape, surface area to volume ratios of cytoplasmic and nuclear compartments, substrate dimensionality, substrate activation area, and substrate stiffness, are all integrated. The resulting model accounts for seemingly contradictory experimental trends and lends new insight into controlling YAP/TAZ signalling.