Physical Sciences Oncology Center at Penn (PSOC@penn), University of Pennsylvania, Philadelphia, PA, USA.
Molecular & Cell Biophysics Lab, University of Pennsylvania, Philadelphia, PA, USA.
Nucleus. 2022 Dec;13(1):129-143. doi: 10.1080/19491034.2022.2045726.
Nuclear rupture has long been associated with deficits or defects in lamins, with recent results also indicating a role for actomyosin stress, but key physical determinants of rupture remain unclear. Here, lamin-B filaments stably interact with the nuclear membrane at sites of low Gaussian curvature yet dilute at high curvature to favor rupture, whereas lamin-A depletion requires high strain-rates. Live-cell imaging of lamin-B1 gene-edited cancer cells is complemented by fixed-cell imaging of rupture in: iPS-derived progeria patients cells, cells within beating chick embryo hearts, and cancer cells with multi-site rupture after migration through small pores. Data fit a model of stiff filaments that detach from a curved surface.Rupture is modestly suppressed by inhibiting myosin-II and by hypotonic stress, which slow the strain-rates. Lamin-A dilution and rupture probability indeed increase above a threshold rate of nuclear pulling. Curvature-sensing mechanisms of proteins at plasma membranes, including Piezo1, might thus apply at nuclear membranes. High nuclear curvature drives lamina dilution and nuclear envelope rupture even when myosin stress is inhibited. Stiff filaments generally dilute from sites of high Gaussian curvature, providing mathematical fits of experiments.
核破裂长期以来一直与核纤层蛋白的缺陷或缺失有关，最近的研究结果也表明肌动球蛋白应激也发挥了作用，但破裂的关键物理决定因素仍不清楚。在这里，核纤层蛋白-B 丝与低高斯曲率处的核膜稳定相互作用，但在高曲率处稀释，以利于破裂，而核纤层蛋白-A 的耗竭需要高应变速率。用编辑 lamin-B1 基因的癌细胞的活细胞成像来补充固定细胞成像，研究对象为：iPS 来源的早衰症患者细胞、搏动的鸡胚心脏细胞、以及在通过小孔迁移后多处破裂的癌细胞。数据符合刚性丝从弯曲表面脱离的模型。通过抑制肌球蛋白-II 和通过低渗应激可以适度抑制破裂，低渗应激会降低应变速率。核牵拉的速率超过阈值时，核纤层蛋白-A 的稀释和破裂概率确实会增加。因此，质膜上的蛋白质（包括 Piezo1）的曲率感应机制可能也适用于核膜。即使抑制肌球蛋白应力，高核曲率也会导致核纤层稀释和核膜破裂。刚性丝通常从高高斯曲率的部位稀释，为实验提供了数学拟合。
