Cells migrate in vivo through complex confining microenvironments, which induce significant nuclear deformation that may lead to nuclear blebbing and nuclear envelope rupture. While actomyosin contractility has been implicated in regulating nuclear envelope integrity, the exact mechanism remains unknown. Here, we argue that confinement-induced activation of RhoA/myosin-II contractility, coupled with LINC complex-dependent nuclear anchoring at the cell posterior, locally increases cytoplasmic pressure and promotes passive influx of cytoplasmic constituents into the nucleus without altering nuclear efflux. Elevated nuclear influx is accompanied by nuclear volume expansion, blebbing, and rupture, ultimately resulting in reduced cell motility. Moreover, inhibition of nuclear efflux is sufficient to increase nuclear volume and blebbing on two-dimensional surfaces, and acts synergistically with RhoA/myosin-II contractility to further augment blebbing in confinement. Cumulatively, confinement regulates nuclear size, nuclear integrity, and cell motility by perturbing nuclear flux homeostasis via a RhoA-dependent pathway.

中文翻译：

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限制通过诱导 RhoA 介导的核流入、体积膨胀和起泡来阻碍运动

细胞在体内迁移通过复杂的限制性微环境，这会引起显着的核变形，可能导致核起泡和核膜破裂。虽然肌动球蛋白收缩性与调节核膜完整性有关，但确切的机制仍不清楚。在这里，我们认为，限制诱导的 RhoA/肌球蛋白-II 收缩性激活，加上细胞后部的 LINC 复合物依赖性核锚定，局部增加细胞质压力并促进细胞质成分被动流入细胞核，而不改变核流出。核流入增加伴随着核体积膨胀、起泡和破裂，最终导致细胞运动性降低。此外，抑制核流出足以增加核体积和二维表面上的起泡，并与 RhoA/肌球蛋白-II 收缩性协同作用，进一步增强限制中的起泡。总的来说，限制通过 RhoA 依赖性途径扰乱核通量稳态来调节核大小、核完整性和细胞运动。