Department of Medicine, Brigham & Women's Hospital/Harvard Medical School, Cambridge, Massachusetts 02139, USA.
J Biol Chem. 2011 Jul 29;286(30):26743-53. doi: 10.1074/jbc.M111.233700. Epub 2011 Jun 7.
Maintaining physical connections between the nucleus and the cytoskeleton is important for many cellular processes that require coordinated movement and positioning of the nucleus. Nucleo-cytoskeletal coupling is also necessary to transmit extracellular mechanical stimuli across the cytoskeleton to the nucleus, where they may initiate mechanotransduction events. The LINC (Linker of Nucleoskeleton and Cytoskeleton) complex, formed by the interaction of nesprins and SUN proteins at the nuclear envelope, can bind to nuclear and cytoskeletal elements; however, its functional importance in transmitting intracellular forces has never been directly tested. This question is particularly relevant since recent findings have linked nesprin mutations to muscular dystrophy and dilated cardiomyopathy. Using biophysical assays to assess intracellular force transmission and associated cellular functions, we identified the LINC complex as a critical component for nucleo-cytoskeletal force transmission. Disruption of the LINC complex caused impaired propagation of intracellular forces and disturbed organization of the perinuclear actin and intermediate filament networks. Although mechanically induced activation of mechanosensitive genes was normal (suggesting that nuclear deformation is not required for mechanotransduction signaling) cells exhibited other severe functional defects after LINC complex disruption; nuclear positioning and cell polarization were impaired in migrating cells and in cells plated on micropatterned substrates, and cell migration speed and persistence time were significantly reduced. Taken together, our findings suggest that the LINC complex is critical for nucleo-cytoskeletal force transmission and that LINC complex disruption can result in defects in cellular structure and function that may contribute to the development of muscular dystrophies and cardiomyopathies.
维持核与细胞骨架之间的物理连接对于许多需要核协调运动和定位的细胞过程非常重要。核骨架连接也需要将细胞外机械刺激通过细胞骨架传递到核内，在核内它们可能引发机械转导事件。LINC（核骨架和细胞骨架的连接）复合物由核膜上 nesprins 和 SUN 蛋白的相互作用形成，可以与核和细胞骨架元件结合；然而，它在传递细胞内力方面的功能重要性从未被直接测试过。这个问题特别重要，因为最近的发现将 nesprin 突变与肌肉萎缩症和扩张型心肌病联系起来。我们使用生物物理测定来评估细胞内力的传递和相关的细胞功能，确定 LINC 复合物是核-细胞骨架力传递的关键组成部分。LINC 复合物的破坏导致细胞内力的传播受损，核周肌动蛋白和中间丝网络的组织紊乱。尽管机械诱导的机械敏感性基因的激活是正常的（表明核变形不是机械转导信号所必需的），但在 LINC 复合物破坏后，细胞表现出其他严重的功能缺陷；在迁移细胞和在微图案化底物上培养的细胞中，核定位和细胞极化受损，细胞迁移速度和持续时间显著降低。总之，我们的研究结果表明，LINC 复合物对于核-细胞骨架力的传递至关重要，LINC 复合物的破坏可能导致细胞结构和功能的缺陷，从而导致肌肉萎缩症和心肌病的发生。
