Infante Elvira, Stannard Andrew, Board Stephanie J, Rico-Lastres Palma, Panagaki Fani, Beedle Amy E M, Rajan Vinoth Sundar, Rostkova Elena, Lezamiz Ainhoa, Wang Yong Jian, Breen Samuel Gulaidi, Shanahan Catherine, Roca-Cusachs Pere, Garcia-Manyes Sergi
Department of Physics and Randall Centre for Cell and Molecular Biophysics, King's College London, WC2R 2LS, London, UK.
Cardiovascular Division, James Black Centre, King's College London, London SE5 9NU, UK Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute of Science and.
Nat Phys. 2019 Sep;15(9):973-981. doi: 10.1038/s41567-019-0551-3. Epub 2019 Jul 1.
The translocation of mechanosensitive transcription factors (TFs) across the nuclear envelope is a crucial step in cellular mechanotransduction. Yet the molecular mechanisms by which external mechanical cues control the nuclear shuttling dynamics of TFs through the nuclear pore complex (NPC) to activate gene expression are poorly understood. Here, we show that the nuclear import rate of myocardin-related transcription factor A (MRTFA) - a protein that regulates cytoskeletal dynamics via the activation of the TF serum response factor (SRF) - inversely correlates with the protein's nanomechanical stability and does not relate to its thermodynamic stability. Tagging MRTFA with mechanically resistant proteins results in the downregulation of SRF-mediated myosin light-chain 9 (MYL9) gene expression and subsequent slowing down of cell migration. We conclude that the mechanical unfolding of proteins regulates their nuclear translocation rate through the NPC, and highlight the role of the NPC as a selective mechanosensor able to discriminate forces as low as ~10 pN. The modulation of the mechanical stability of TFs may represent a new strategy for the control of gene expression.
机械敏感转录因子（TFs）穿过核膜的转位是细胞机械转导中的关键步骤。然而，外界机械信号通过核孔复合体（NPC）控制TFs的核穿梭动力学以激活基因表达的分子机制仍知之甚少。在此，我们表明心肌素相关转录因子A（MRTFA）——一种通过激活TF血清反应因子（SRF）来调节细胞骨架动力学的蛋白质——的核输入速率与其纳米机械稳定性呈负相关，而与其热力学稳定性无关。用机械抗性蛋白标记MRTFA会导致SRF介导的肌球蛋白轻链9（MYL9）基因表达下调，并随后减缓细胞迁移。我们得出结论，蛋白质的机械展开调节其通过NPC的核转位速率，并强调NPC作为一种能够区分低至约10皮牛顿力的选择性机械传感器的作用。TFs机械稳定性的调节可能代表了一种控制基因表达的新策略。
