Ferreira Paulo A
Department of Ophthalmology, Department of Pathology, Duke University Medical Center, NC, Durham, USA.
FEBS Lett. 2023 Oct;597(20):2567-2589. doi: 10.1002/1873-3468.14722. Epub 2023 Aug 24.
Nucleocytoplasmic transport comprises the multistep assembly, transport, and disassembly of protein and RNA cargoes entering and exiting nuclear pores. Accruing evidence supports that impairments to nucleocytoplasmic transport are a hallmark of neurodegenerative diseases. These impairments cause dysregulations in nucleocytoplasmic partitioning and proteostasis of nuclear transport receptors and client substrates that promote intracellular deposits - another hallmark of neurodegeneration. Disturbances in liquid-liquid phase separation (LLPS) between dense and dilute phases of biomolecules implicated in nucleocytoplasmic transport promote micrometer-scale coacervates, leading to proteinaceous aggregates. This Review provides historical and emerging principles of LLPS at the interface of nucleocytoplasmic transport, proteostasis, aging and noxious insults, whose dysregulations promote intracellular aggregates. E3 SUMO-protein ligase Ranbp2 constitutes the cytoplasmic filaments of nuclear pores, where it acts as a molecular hub for rate-limiting steps of nucleocytoplasmic transport. A vignette is provided on the roles of Ranbp2 in nucleocytoplasmic transport and at the intersection of proteostasis in the survival of photoreceptor and motor neurons under homeostatic and pathophysiological environments. Current unmet clinical needs are highlighted, including therapeutics aiming to manipulate aggregation-dissolution models of purported neurotoxicity in neurodegeneration.
核质运输包括进出核孔的蛋白质和RNA货物的多步骤组装、运输和拆卸。越来越多的证据支持，核质运输受损是神经退行性疾病的一个标志。这些损伤会导致核质分配失调以及核运输受体和客户底物的蛋白质稳态失调，从而促进细胞内沉积物的形成——这是神经退行性变的另一个标志。参与核质运输的生物分子在浓相和稀相之间的液-液相分离（LLPS）紊乱会促进微米级凝聚物的形成，导致蛋白质聚集体。本综述阐述了核质运输、蛋白质稳态、衰老和有害损伤界面处LLPS的历史和新出现的原理，其失调会促进细胞内聚集体的形成。E3 SUMO蛋白连接酶Ranbp2构成核孔的细胞质细丝，在那里它作为核质运输限速步骤的分子枢纽。本文介绍了Ranbp2在核质运输中的作用，以及在稳态和病理生理环境下，在光感受器和运动神经元存活过程中蛋白质稳态交叉点上的作用。文中强调了当前未满足的临床需求，包括旨在操纵神经退行性变中所谓神经毒性的聚集-溶解模型的治疗方法。
