Institute for Biophysical Chemistry, Hannover Medical School, Hannover, Germany.
Department of NanoBiophotonics, Max Planck Institute for Multidisciplinary Sciences, Göttingen, Germany.
Sci Adv. 2024 Nov;10(44):eadp5929. doi: 10.1126/sciadv.adp5929. Epub 2024 Oct 30.
Cortical formins, pivotal for the assembly of linear actin filaments beneath the membrane, exert only minor effects on unconfined cell migration of weakly and moderately adherent cells. However, their impact on migration and mechanostability of highly adherent cells remains poorly understood. Here, we demonstrate that loss of cortical actin filaments generated by the formins mDia1 and mDia3 drastically compromises cell migration and mechanics in highly adherent fibroblasts. Biophysical analysis of the mechanical properties of the mutant cells revealed a markedly softened cell cortex in the poorly adherent state. Unexpectedly, in the highly adherent state, associated with a hyperstretched morphology with exaggerated focal adhesions and prominent high-strain stress fibers, they exhibited even higher cortical tension compared to control. Notably, misguidance of intracellular forces, frequently accompanied by stress-fiber rupture, culminated in the formation of tension- and contractility-induced macroapertures, which was instantly followed by excessive lamellipodial protrusion at the periphery, providing critical insights into mechanotransduction of mechanically stressed and highly adherent cells.
皮层形成蛋白对于膜下线性肌动蛋白丝的组装至关重要，但对弱黏附和中度黏附细胞的无约束迁移的影响较小。然而，它们对高度黏附细胞迁移和机械稳定性的影响仍知之甚少。在这里，我们证明了由formin mDia1 和 mDia3 产生的皮层肌动蛋白丝的缺失会严重影响高度黏附成纤维细胞的迁移和力学性能。对突变细胞力学特性的生物物理分析表明，在低黏附状态下，细胞皮层明显变软。出乎意料的是，在高黏附状态下，与超拉伸形态相关，伴有夸张的焦点粘连和明显的高应变应力纤维，与对照相比，它们表现出更高的皮层张力。值得注意的是，细胞内力的错误引导，经常伴随着应力纤维的断裂，最终导致张力和收缩诱导的大孔的形成，这立即导致边缘处过度的片状伪足伸出，为机械应激和高度黏附细胞的机械转导提供了关键的见解。
