Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Joint first authors.
Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Biochemistry and Molecular Biophysics Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Joint first authors.
Trends Cell Biol. 2019 Apr;29(4):308-322. doi: 10.1016/j.tcb.2018.12.004. Epub 2019 Jan 16.
Nuclear-import receptors (NIRs) bind nuclear-localization signals (NLSs) of protein cargo in the cytoplasm and transport them into the nucleus. Here, we review advances establishing that NIRs also function in the cytoplasm to prevent and reverse functional and aberrant phase transitions of their cargo, including neurodegenerative disease-linked RNA-binding proteins (RBPs) with prion-like domains, such as TDP-43, FUS, hnRNPA1, and hnRNPA2. NIRs selectively extract cargo from condensed liquid phases thereby regulating functional phase separation. Consequently, NIRs sculpt cytoplasmic membraneless organelles and regulate cellular organization beyond their canonical role in nuclear import. Elevating NIR expression dissolves cytoplasmic RBP aggregates, restores functional RBPs to the nucleus, and rescues disease-linked RBP toxicity. Thus, NIRs could be leveraged therapeutically to restore RBP homeostasis and mitigate neurodegeneration.
核输入受体 (NIRs) 在细胞质中结合蛋白货物的核定位信号 (NLSs)，并将其运输到细胞核内。在这里，我们回顾了一些进展，这些进展确立了 NIRs 也在细胞质中发挥作用，以防止和逆转其货物（包括具有朊病毒样结构域的神经退行性疾病相关 RNA 结合蛋白 (RBPs)）的功能和异常相变，这些货物包括 TDP-43、FUS、hnRNPA1 和 hnRNPA2。NIRs 选择性地从浓缩的液相中提取货物，从而调节功能相分离。因此，NIRs 塑造了细胞质无膜细胞器，并调节了细胞组织，超出了它们在核输入中的典型作用。提高 NIR 的表达可以溶解细胞质中的 RBP 聚集体，将功能性 RBP 恢复到细胞核中，并挽救与疾病相关的 RBP 毒性。因此，NIRs 可以被利用来治疗以恢复 RBP 平衡和减轻神经退行性变。
