Institute for Medicine and Engineering, University of Pennsylvania, Philadelphia, PA.
Physics Department, Syracuse University, Syracuse, NY.
J Cell Biol. 2019 Dec 2;218(12):4079-4092. doi: 10.1083/jcb.201902046. Epub 2019 Nov 1.
Mammalian cells frequently migrate through tight spaces during normal embryogenesis, wound healing, diapedesis, or in pathological situations such as metastasis. Nuclear size and shape are important factors in regulating the mechanical properties of cells during their migration through such tight spaces. At the onset of migratory behavior, cells often initiate the expression of vimentin, an intermediate filament protein that polymerizes into networks extending from a juxtanuclear cage to the cell periphery. However, the role of vimentin intermediate filaments (VIFs) in regulating nuclear shape and mechanics remains unknown. Here, we use wild-type and vimentin-null mouse embryonic fibroblasts to show that VIFs regulate nuclear shape and perinuclear stiffness, cell motility in 3D, and the ability of cells to resist large deformations. These changes increase nuclear rupture and activation of DNA damage repair mechanisms, which are rescued by exogenous reexpression of vimentin. Our findings show that VIFs provide mechanical support to protect the nucleus and genome during migration.
哺乳动物细胞在正常胚胎发生、创伤愈合、血行转移或转移等病理情况下经常穿过狭小的空间迁移。核的大小和形状是调节细胞在穿过这些狭小空间时机械特性的重要因素。在迁移行为开始时，细胞通常会启动波形蛋白的表达，波形蛋白是一种中间丝蛋白，它聚合形成从核周笼延伸到细胞外周的网络。然而，中间丝蛋白 (VIFs) 在调节核形状和力学方面的作用尚不清楚。在这里，我们使用野生型和波形蛋白缺失的小鼠胚胎成纤维细胞表明 VIFs 调节核的形状和核周硬度、细胞在 3D 中的迁移能力以及细胞抵抗大变形的能力。这些变化增加了核破裂和 DNA 损伤修复机制的激活，而外源重新表达波形蛋白可以挽救这些变化。我们的研究结果表明，VIFs 在迁移过程中提供机械支持以保护核和基因组。
