<br>核周肌动蛋白帽与核力学在调节流诱导 Yap 时空核质转运中的耦合,Advanced Science

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核周肌动蛋白帽与核力学在调节流诱导 Yap 时空核质转运中的耦合
Advanced Science ( IF 14.3 ) Pub Date : 2023-12-31 , DOI: 10.1002/advs.202305867
Tianxiang Ma ₁ , Xiao Liu ₁ , Haoran Su ₁ , Qiusheng Shi ₁ , Yuan He ₁ , Fan Wu ₁ , Chenxing Gao ₁ , Kexin Li ₁ , Zhuqing Liang ₁ , Dongrui Zhang ₁ , Xing Zhang ₁ , Ke Hu ₁ , Shangyu Li _{2,

3} , Li Wang ₁ , Min Wang ₄ , Shuhua Yue ₁ , Weili Hong ₁ , Xun Chen ₁ , Jing Zhang ₁ , Lisha Zheng ₁ , Xiaoyan Deng ₁ , Pu Wang ₁ , Yubo Fan _{1,

5}

Affiliation

包括流动剪切应力在内的机械力通过调节 Yes 相关蛋白 (YAP) 等转录因子的核细胞质转运来控制基本的细胞过程。然而，潜在的机械机制仍然难以捉摸。在这项研究中，据报道，单向流诱导双相 YAP 运输，最初是核输入，然后是肌动蛋白帽形成和核硬化的核输出。相反，病理性振荡流诱导轻微的肌动蛋白帽形成、核软化和持续的 YAP 核定位。为了阐明不同的 YAP 时空分布，开发了一个 3D 机械化学模型，该模型集成了流量传感、细胞骨架组织、细胞核机械转导和 YAP 运输。结果表明，尽管肌动蛋白帽施加了显着的局部核应力，但其固有的刚度抵消了传统纤维对核膜施加的分散收缩应力。此外，核硬度的变化协同调节核变形，从而控制 YAP 运输。此外，通过将单细胞模型扩展到集体顶点框架，发现单个细胞内肌动蛋白帽形成的不规则性有可能引起细胞单层中的拓扑缺陷和空间异质YAP分布。这项工作揭示了流诱导核细胞质运输的统一机制，提供了转录因子定位和机械刺激之间的联系。

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Coupling of Perinuclear Actin Cap and Nuclear Mechanics in Regulating Flow-Induced Yap Spatiotemporal Nucleocytoplasmic Transport

Mechanical forces, including flow shear stress, govern fundamental cellular processes by modulating nucleocytoplasmic transport of transcription factors like Yes-associated Protein (YAP). However, the underlying mechanical mechanism remains elusive. In this study, it is reported that unidirectional flow induces biphasic YAP transport with initial nuclear import, followed by nuclear export as actin cap formation and nuclear stiffening. Conversely, pathological oscillatory flow induces slight actin cap formation, nuclear softening, and sustained YAP nuclear localization. To elucidate the disparately YAP spatiotemporal distribution, a 3D mechanochemical model is developed, which integrates flow sensing, cytoskeleton organization, nucleus mechanotransduction, and YAP transport. The results unveiled that despite the significant localized nuclear stress imposed by the actin cap, its inherent stiffness counteracts the dispersed contractile stress exerted by conventional fibers on the nuclear membrane. Moreover, alterations in nuclear stiffness synergistically regulate nuclear deformation, thereby governing YAP transport. Furthermore, by expanding the single-cell model to a collective vertex framework, it is revealed that the irregularities in actin cap formation within individual cells have the potential to induce topological defects and spatially heterogeneous YAP distribution in the cellular monolayer. This work unveils a unified mechanism of flow-induced nucleocytoplasmic transport, providing a linkage between transcription factor localization and mechanical stimulation.

更新日期：2023-12-31

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