Mechanical force controls fundamental cellular processes in health and disease, and increasing evidence shows that the nucleus both experiences and senses applied forces. Such forces can lead to the nuclear translocation of proteins, but whether force controls nucleocytoplasmic transport, and how, remains unknown. Here we show that nuclear forces differentially control 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 for facilitated diffusion. Owing to this differential effect, force leads to the translocation of cargoes into or out of the nucleus 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 unveils a mechanism of mechanically induced signalling, probably operating in parallel with others, with potential applicability across signalling pathways.

机械力控制着健康和疾病的基本细胞过程，越来越多的证据表明，细胞核既能感受也能感知所施加的力。这种力可以导致蛋白质的核易位，但力是否控制核细胞质运输以及如何控制仍然未知。在这里，我们表明核力有差别地控制被动和促进核质运输，为穿梭蛋白质的机械敏感性设定规则。我们证明，核力增加了核孔复合物的渗透性，其对分子量的依赖性对于被动扩散比对于促进扩散更强。由于这种不同的效应，力导致货物在给定的分子量和对核转运受体的亲和力范围内易位进或出核。此外，我们表明，几种转录调节因子的机械敏感性既可以用这种机制来解释，也可以通过引入适当的核定位信号进行外源工程设计。我们的工作揭示了一种机械诱导信号传导机制，可能与其他信号传导并行运作，具有跨信号传导途径的潜在适用性。