Donnaloja F, Jacchetti E, Soncini M, Raimondi M T
Department of Chemistry, Materials and Chemical Engineering "Giulio Natta," Politecnico di Milano, Milan, Italy.
Department of Electronics, Information and Bioengineering, Politecnico di Milano, Milan, Italy.
Front Physiol. 2019 Jul 12;10:896. doi: 10.3389/fphys.2019.00896. eCollection 2019.
Cell fate is correlated to mechanotransduction, in which forces transmitted by the cytoskeleton filaments alter the nuclear shape, affecting transcription factor import/export, cells transcription activity and chromatin distribution. There is in fact evidence that stem cells cultured in 3D environments mimicking the native niche are able to maintain their stemness or modulate their cellular function. However, the molecular and biophysical mechanisms underlying cellular mechanosensing are still largely unclear. The propagation of mechanical stimuli via a direct pathway from cell membrane integrins to SUN proteins residing in the nuclear envelop has been demonstrated, but we suggest that the cells' fate is mainly affected by the force distribution at the nuclear envelope level, where the SUN protein transmits the stimuli via its mechanical connection to several cell structures such as chromatin, lamina and the nuclear pore complex (NPC). In this review, we analyze the NPC structure and organization, which have not as yet been fully investigated, and its plausible involvement in cell fate. NPC is a multiprotein complex that spans the nuclear envelope, and is involved in several key cellular processes such as bidirectional nucleocytoplasmic exchange, cell cycle regulation, kinetochore organization, and regulation of gene expression. As several connections between the NPC and the nuclear envelope, chromatin and other transmembrane proteins have been identified, it is reasonable to suppose that nuclear deformations can alter the NPC structure. We provide evidence that the transmission of mechanical forces may significantly affects the basket conformation via the Nup153-SUN1 connection, both altering the passage of molecules through it and influencing the state of chromatin packing. Finally, we review the known correlations between a pathological NPC structure and diseases such as cancer, autoimmune disease, aging and laminopathies.
细胞命运与机械转导相关，在机械转导过程中，细胞骨架细丝传递的力会改变细胞核形状，影响转录因子的进出、细胞转录活性和染色质分布。事实上，有证据表明，在模拟天然微环境的三维环境中培养的干细胞能够维持其干性或调节其细胞功能。然而，细胞机械传感的分子和生物物理机制仍不清楚。机械刺激通过从细胞膜整合素到位于核膜的SUN蛋白的直接途径进行传播，这一点已得到证实，但我们认为，细胞命运主要受核膜水平的力分布影响，在核膜水平，SUN蛋白通过其与染色质、核纤层和核孔复合体（NPC）等几种细胞结构的机械连接来传递刺激。在这篇综述中，我们分析了尚未得到充分研究的NPC结构和组织，以及它可能在细胞命运中的作用。NPC是一种跨越核膜的多蛋白复合体，参与双向核质交换、细胞周期调控、动粒组织和基因表达调控等几个关键的细胞过程。由于已确定NPC与核膜、染色质和其他跨膜蛋白之间存在多种联系，因此可以合理推测核变形会改变NPC结构。我们提供的证据表明，机械力的传递可能通过Nup153-SUN1连接显著影响篮状结构，既改变分子通过它的通道，又影响染色质包装状态。最后，我们综述了病理性NPC结构与癌症、自身免疫性疾病、衰老和核纤层蛋白病等疾病之间的已知关联。
