Confinement hinders motility by inducing RhoA-mediated nuclear influx, volume expansion, and blebbing
Confinement hinders motility by inducing RhoA-mediated nuclear influx, volume expansion, and blebbing
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DOI：
10.1083/jcb.201902057
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发表时间：
2019-12-01
影响因子：
7.8
通讯作者：
Konstantopoulos, Konstantinos
中科院分区：
文献类型：
--
作者：
Mistriotis, Panagiotis;Wisniewski, Emily O.;Konstantopoulos, Konstantinos
细胞在体内通过复杂的限制性微环境迁移，这诱导显著的核变形，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，约束诱导的激活RhoA/肌球蛋白-II收缩，加上LINC复合物依赖的核锚定在细胞后部，局部增加细胞质的压力，促进细胞质成分被动流入细胞核，而不改变核流出。升高的核内流伴随着核体积膨胀、起泡和破裂，最终导致细胞运动性降低。此外，抑制核外排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，以进一步增加限制中的起泡。累积起来，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性。
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.