Amyloid domains in the cell nucleus controlled by nucleoskeletal protein lamin B1 reveal a new pathway of mercury neurotoxicity
Amyloid domains in the cell nucleus controlled by nucleoskeletal protein lamin B1 reveal a new pathway of mercury neurotoxicity
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细胞核中由核骨架蛋白核纤层蛋白B1控制的淀粉样蛋白结构域揭示了汞神经毒性的新途径
DOI：
10.7717/peerj.754/fig-4
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发表时间：
2015
期刊：
影响因子：
2.7
通讯作者：
A. von Mikecz
中科院分区：
文献类型：
--
作者：
Florian Arnhold;K. Gührs;A. von Mikecz
汞 (Hg) 是一种生物蓄积性微量金属，以元素、无机和有机化学形式在全球大气和水中循环。虽然汞是一种臭名昭著的神经毒物，但其潜在的细胞途径尚不清楚。我们将细胞核中的淀粉样蛋白聚集确定为汞生物相互作用的新途径。通过纯化蛋白质聚集体的质谱分析，检测到剪接体成分和核骨架蛋白核纤层蛋白 B1 的子集是汞诱导的核聚集体网络的组成部分。通过淀粉样蛋白特异性抗体和染料对剪接斑点内淀粉样蛋白核心的共聚焦成像来定位聚集体网络，这些剪接斑点另外招募泛素-蛋白酶体系统的成分。汞显着增强细胞核中的整体蛋白酶体活性，表明淀粉样蛋白斑点的形成在维持蛋白质稳态中发挥作用。 RNAi 敲除表明核纤层蛋白 B1 调节淀粉样蛋白斑点的形成，因此同样参与核蛋白稳态。由于汞诱导的核骨架和蛋白质稳态之间的相互作用级联减少了神经元信号传导，细胞核中的淀粉样纤维颤动被引入作为汞神经毒性的一个特征，这为未来研究开辟了新的途径。与细胞质中受细胞骨架控制的蛋白质聚集事件类似，核蛋白的淀粉样蛋白纤维化可能是由核骨架驱动的。
Mercury (Hg) is a bioaccumulating trace metal that globally circulates the atmosphere and waters in its elemental, inorganic and organic chemical forms. While Hg represents a notorious neurotoxicant, the underlying cellular pathways are insufficiently understood. We identify amyloid protein aggregation in the cell nucleus as a novel pathway of Hg-bio-interactions. By mass spectrometry of purified protein aggregates, a subset of spliceosomal components and nucleoskeletal protein lamin B1 were detected as constituent parts of an Hg-induced nuclear aggregome network. The aggregome network was located by confocal imaging of amyloid-specific antibodies and dyes to amyloid cores within splicing-speckles that additionally recruit components of the ubiquitin-proteasome system. Hg significantly enhances global proteasomal activity in the nucleus, suggesting that formation of amyloid speckles plays a role in maintenance of protein homeostasis. RNAi knock down showed that lamin B1 for its part regulates amyloid speckle formation and thus likewise participates in nuclear protein homeostasis. As the Hg-induced cascade of interactions between the nucleoskeleton and protein homeostasis reduces neuronal signalling, amyloid fibrillation in the cell nucleus is introduced as a feature of Hg-neurotoxicity that opens new avenues of future research. Similar to protein aggregation events in the cytoplasm that are controlled by the cytoskeleton, amyloid fibrillation of nuclear proteins may be driven by the nucleoskeleton.
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影响因子：
2.9
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