Aggregation of RNA-binding proteins (RBPs) is a pathological hallmark of neurodegenerative disorders like amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). In these diseases, TDP-43 and FUS RBPs are depleted from the nuclear compartment, where they are normally localized, and found within cytoplasmic inclusions in degenerating regions of affected individuals’ postmortem tissue. The mechanisms responsible for aggregation of these proteins has remained elusive, but recent studies suggest liquid-liquid phase separation (LLPS) might serve as a critical nucleation step in formation of pathological inclusions. The process of phase separation also underlies the formation and maintenance of several functional membraneless organelles (MLOs) throughout the cell, some of which contain TDP-43, FUS, and other disease-linked RBPs. One common ligand of disease-linked RBPs, RNA, is a major component of MLOs containing RBPs and has been demonstrated to be a strong modulator of RBP phase transitions. Although early evidence suggested a largely synergistic effect of RNA on RBP phase separation and MLO assembly, recent work indicates that RNA can also antagonize RBP phase behavior under certain physiological and pathological conditions. In this review, we describe the mechanisms underlying RNA-mediated phase transitions of RBPs and examine the molecular properties of these interactions, such as RNA length, sequence, and secondary structure, that mediate physiological or pathological LLPS.

RNA 结合蛋白 (RBP) 的聚集是肌萎缩侧索硬化症 (ALS) 和额颞叶痴呆 (FTD) 等神经退行性疾病的病理标志。在这些疾病中，TDP-43 和 FUS RBP 从通常定位的核区室中耗尽，并在受影响个体死后组织退化区域的细胞质内含物中发现。导致这些蛋白质聚集的机制仍然难以捉摸，但最近的研究表明液-液相分离（LLPS）可能是形成病理内含物的关键成核步骤。相分离过程也是细胞内多种功能性无膜细胞器 (MLO) 形成和维持的基础，其中一些细胞器含有 TDP-43、FUS 和其他与疾病相关的 RBP。与疾病相关的 RBP 的一种常见配体 RNA 是含有 RBP 的 MLO 的主要成分，并已被证明是 RBP 相变的强大调节剂。尽管早期证据表明 RNA 对 RBP 相分离和 MLO 组装具有很大的协同作用，但最近的研究表明 RNA 在某些生理和病理条件下也可以拮抗 RBP 相行为。在这篇综述中，我们描述了 RNA 介导的 RBP 相变的机制，并检查了这些相互作用的分子特性，例如介导生理或病理 LLPS 的 RNA 长度、序列和二级结构。