Mechanosensitivity of nucleocytoplasmic transport

Abstract

Mechanical force controls fundamental cellular processes in health and disease, and increasing evidence shows that the nucleus both experiences and senses applied forces. Here we show that nuclear forces differentially control both passive and facilitated nucleocytoplasmic transport, setting the rules for the mechanosensitivity of shuttling proteins. We demonstrate that nuclear force increases permeability across nuclear pore complexes, with a dependence on molecular weight that is stronger for passive than facilitated diffusion. Due to this differential effect, force leads to the translocation into or out of the nucleus of cargoes within a given range of molecular weight and affinity for nuclear transport receptors. Further, we show that the mechanosensitivity of several transcriptional regulators can be both explained by this mechanism, and engineered exogenously by introducing appropriate nuclear localization signals. Our work sets a novel framework to understand mechanically induced signalling, with potential general applicability across signalling pathways and pathophysiological scenarios.

Force-biased nuclear import sets nuclear-cytoplasmic volumetric coupling by osmosis

“…This model, calibrated with data from refs. ( 17, 25 ), suggests that moderate tension changes may affect nuclear size through this effect (SI appendix and Fig 4A-B and S3E). Hence, we tested this hypothesis experimentally.…”

“…Here, time progression is coded with a color gradient (from light to dark). The green and orange solid lines are predictions from the theoretical model with parameter values: 20\% fraction NLS/NES proteins (in absence of applied tension), and an external tension-transport bias of 4 10 3 m/N (estimated from Andreu et al 2021). The orange line is a prediction for a variation of the tension caused by external forces σ ext from 0 to 10 −4 N/m.…”

“…This is equivalent to order 50.000 motors exerting pN forces. However, these forces on the nucleus would be observed also by traction force microscopy, by Newton’s third law. Given these considerations, we have considered a range of 10 −6 to 10 −3 N/m for both constitutive and applied mechanical tensions, and we consider that a realistic range for tensions on the nucleus applied by the cytoskeleton could be 10 −5 – 10 −4 N/m. In order to fix the bias parameter in the model variant with force-biased transport, we used the data provided by Andreu and coworkers (Andreu et al, 2021). In this study (Fig 2I of the paper), the authors find a change in the concentration of nuclearly localized proteins c N by a factor of 3/2 by using gels of stiffness from 1.5 to 30 kPa.…”

“…Based on the model, we reasoned that this was very unlikely to be a direct effect, as the direction of the effect is opposite to the expectation from cytoskeletal compressive forces ( 24 ), and the mechanical forces required to change nuclear size would be abnormally large (see SI appendix). Instead, recent findings suggest that NE tension, controlling nuclear pore size, could alter nuclear import rate of small proteins( 25–28 ) potentially affecting osmosis ( 29 ).…”

“…The plot reports the predicted fold change in nuclear volume (y axis) for increasing applied extensile tension σ ext . Parameter values: cytoplasmic volume V C = 2000 μ m 3 , 20% fraction NLS/NES proteins in absence of applied tension, and a tension-transport bias of η = 4 10 3 m/N (estimated from Andreu et al 2021 ( 26 ), see SI appendix). This model neglects direct effect of extensile tension on nuclear size.…”