IFOM (Foundation FIRC Institute of Molecular Oncology), via Adamello 16, 20139, Milan, Italy.
National Medical Research Center of Cardiology, 3rd Cherepkovskaya Street, 15a, 121552, Moscow, Russia.
Commun Biol. 2022 May 12;5(1):456. doi: 10.1038/s42003-022-03406-9.
Mechanosignaling, initiated by extracellular forces and propagated through the intracellular cytoskeletal network, triggers signaling cascades employed in processes as embryogenesis, tissue maintenance and disease development. While signal transduction by transcription factors occurs downstream of cellular mechanosensing, little is known about the cell intrinsic mechanisms that can regulate mechanosignaling. Here we show that transcription factor PREP1 (PKNOX1) regulates the stiffness of the nucleus, the expression of LINC complex proteins and mechanotransduction of YAP-TAZ. PREP1 depletion upsets the nuclear membrane protein stoichiometry and renders nuclei soft. Intriguingly, these cells display fortified actomyosin network with bigger focal adhesion complexes resulting in greater traction forces at the substratum. Despite the high traction, YAP-TAZ translocation is impaired indicating disrupted mechanotransduction. Our data demonstrate mechanosignaling upstream of YAP-TAZ and suggest the existence of a transcriptional mechanism actively regulating nuclear membrane homeostasis and signal transduction through the active engagement/disengagement of the cell from the extracellular matrix.
机械信号转导由细胞外力引发，并通过细胞内细胞骨架网络传播，触发胚胎发生、组织维持和疾病发展等过程中使用的信号级联反应。虽然转录因子的信号转导发生在细胞机械感受器的下游，但对于可以调节机械信号转导的细胞内在机制知之甚少。在这里，我们表明转录因子 PREP1（PKNOX1）调节核的硬度、LINC 复合物蛋白的表达和 YAP-TAZ 的机械转导。PREP1 耗竭会破坏核膜蛋白的化学计量平衡，使核变软。有趣的是，这些细胞显示出加固的肌动球蛋白网络，带有更大的焦点粘附复合物，导致基质上的牵引力更大。尽管牵引力很大，但 YAP-TAZ 的易位受损表明机械信号转导受损。我们的数据表明 YAP-TAZ 的机械信号转导上游，并表明存在一种转录机制，通过细胞与细胞外基质的主动结合/脱离，积极调节核膜动态平衡和信号转导。
