The keratin network of intermediate filaments regulates keratinocyte rigidity sensing and nuclear mechanotransduction.
The keratin network of intermediate filaments regulates keratinocyte rigidity sensing and nuclear mechanotransduction.
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DOI：
10.1126/sciadv.abd6187
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发表时间：
2021-01
期刊：
影响因子：
13.6
通讯作者：
Connelly JT
中科院分区：
文献类型：
--
作者：
Laly AC;Sliogeryte K;Pundel OJ;Ross R;Keeling MC;Avisetti D;Waseem A;Gavara N;Connelly JT
与起泡性皮肤病相关的角蛋白缺陷改变了向细胞核的力传递。中间丝的角蛋白网络为角质形成细胞提供了必要的机械强度和弹性，但对机械传感的贡献仍然知之甚少。在这里，我们调查的角蛋白细胞骨架的作用，在响应改变矩阵刚度。我们发现，角质形成细胞适应增加基质刚度形成一个刚性的，相互连接的角蛋白束网络，结合F-肌动蛋白应力纤维的形成和增加细胞刚度。通过显性角蛋白14突变R416 P的过度表达破坏角蛋白稳定性抑制了对基底刚度的正常机械反应，降低了F-肌动蛋白应力纤维和细胞刚度。R416 P突变也损害了机械转导到核纤层，这介导了硬度依赖性染色质重塑。相比之下，细胞连接蛋白的耗竭具有相反的作用，并促进了机械反应性的增加和核纤层蛋白A/C的上调。总之，这些结果表明，角蛋白细胞骨架在基质刚性传感和下游信号转导中起着关键作用。
Keratin defects associated with blistering skin diseases alter force transmission to the nucleus. The keratin network of intermediate filaments provides keratinocytes with essential mechanical strength and resilience, but the contribution to mechanosensing remains poorly understood. Here, we investigated the role of the keratin cytoskeleton in the response to altered matrix rigidity. We found that keratinocytes adapted to increasing matrix stiffness by forming a rigid, interconnected network of keratin bundles, in conjunction with F-actin stress fiber formation and increased cell stiffness. Disruption of keratin stability by overexpression of the dominant keratin 14 mutation R416P inhibited the normal mechanical response to substrate rigidity, reducing F-actin stress fibers and cell stiffness. The R416P mutation also impaired mechanotransduction to the nuclear lamina, which mediated stiffness-dependent chromatin remodeling. By contrast, depletion of the cytolinker plectin had the opposite effect and promoted increased mechanoresponsiveness and up-regulation of lamin A/C. Together, these results demonstrate that the keratin cytoskeleton plays a key role in matrix rigidity sensing and downstream signal transduction.
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DOI：
10.1016/j.jmbbm.2016.02.019
发表时间：
2016-07-01
影响因子：
3.9
作者：
Delaine-Smith, R. M.;Burney, S.;Knight, M. M.
通讯作者：
Knight, M. M.
影响因子：
4
作者：
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影响因子：
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通讯作者：
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影响因子：
3.6
作者：
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通讯作者：
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影响因子：
6.5
作者：
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通讯作者：
Torma, Hans