RNA and membraneless organelles Membraneless compartments can form in cells through liquidliquid phase separation (see the Perspective by Polymenidou). But what prevents these cellular condensates from randomly fusing together? Using the RNA-binding protein (RBP) Whi3, Langdon et al. demonstrated that the secondary structure of different RNA components determines the distinct biophysical and biological properties of the two types of condensates that Whi3 forms. Several RBPs, such as FUS and TDP43, contain prion-like domains and are linked to neurodegenerative diseases. These RBPs are usually soluble in the nucleus but can form pathological aggregates in the cytoplasm. Maharana et al. showed that local RNA concentrations determine distinct phase separation behaviors in different subcellular locations. The higher RNA concentrations in the nucleus act as a buffer to prevent phase separation of RBPs; when mislocalized to the cytoplasm, lower RNA concentrations trigger aggregation. Science, this issue p. 922, p. 918; see also p. 859 High concentrations of RNA prevent pathological aggregation of RNA binding proteins in the nucleus. Prion-like RNA binding proteins (RBPs) such as TDP43 and FUS are largely soluble in the nucleus but form solid pathological aggregates when mislocalized to the cytoplasm. What keeps these proteins soluble in the nucleus and promotes aggregation in the cytoplasm is still unknown. We report here that RNA critically regulates the phase behavior of prion-like RBPs. Low RNA/protein ratios promote phase separation into liquid droplets, whereas high ratios prevent droplet formation in vitro. Reduction of nuclear RNA levels or genetic ablation of RNA binding causes excessive phase separation and the formation of cytotoxic solid-like assemblies in cells. We propose that the nucleus is a buffered system in which high RNA concentrations keep RBPs soluble. Changes in RNA levels or RNA binding abilities of RBPs cause aberrant phase transitions.

中文翻译：

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RNA 缓冲类朊病毒 RNA 结合蛋白的相分离行为


RNA 和无膜细胞器 无膜区室可以通过液液相分离在细胞中形成（参见 Polymenidou 的观点）。但是是什么阻止这些细胞凝聚物随机融合在一起呢？ Langdon 等人使用 RNA 结合蛋白 (RBP) Whi3。证明不同 RNA 成分的二级结构决定了 Whi3 形成的两种类型的凝聚物的不同生物物理和生物学特性。一些 RBP，例如 FUS 和 TDP43，含有类似朊病毒的结构域，与神经退行性疾病有关。这些 RBP 通常可溶于细胞核，但可以在细胞质中形成病理性聚集体。马哈拉纳等人。结果表明，局部 RNA 浓度决定了不同亚细胞位置的不同相分离行为。细胞核中较高的 RNA 浓度充当缓冲剂，防止 RBP 发生相分离；当错误定位到细胞质时，较低的 RNA 浓度会引发聚集。科学，本期第 14 页。 922，p。 918；另见 p. 859 高浓度的 RNA 可防止细胞核中 RNA 结合蛋白的病理性聚集。 TDP43 和 FUS 等朊病毒样 RNA 结合蛋白 (RBP) 大部分可溶于细胞核，但当错误定位到细胞质时会形成固体病理聚集体。是什么使这些蛋白质保持在细胞核中可溶并促进细胞质中的聚集仍然未知。我们在此报道，RNA 严格调节朊病毒样 RBP 的相行为。低RNA/蛋白质比率促进相分离成液滴，而高比率则阻止液滴在体外形成。核RNA水平的降低或RNA结合的基因消除会导致细胞内过度相分离和细胞毒性固体样组装体的形成。 我们认为细胞核是一个缓冲系统，高 RNA 浓度使 RBP 保持可溶。 RBP 的 RNA 水平或 RNA 结合能力的变化会导致异常的相变。