Center for Human Technologies, Istituto Italiano di Tecnologia, Via Enrico Melen 83, 16153, Genoa, Italy.
Department of Biology and Biotechnologies "C. Darwin", Sapienza University of Rome, Piazzale Aldo Moro 5, 00185, Rome, Italy.
Nucleic Acids Res. 2024 Nov 27;52(21):13269-13289. doi: 10.1093/nar/gkae942.
Stress granules (SG) are part of a cellular protection mechanism where untranslated messenger RNAs and RNA-binding proteins are stored upon conditions of cellular stress. Compositional variations due to qualitative or quantitative protein changes can disrupt their functionality and alter their structure. This is the case of different forms of amyotrophic lateral sclerosis (ALS) where a causative link has been proposed between the cytoplasmic de-localization of mutant proteins, such as FUS (Fused in Sarcoma), and the formation of cytotoxic inclusions. Here, we describe the SG transcriptome in neuroblastoma cells and define several features for RNA recruitment in these condensates. We demonstrate that SG dynamics and RNA content are strongly modified by the incorporation of mutant FUS, switching to a more unstructured, AU-rich SG transcriptome. Moreover, we show that mutant FUS, together with its protein interactors and their target RNAs, are responsible for the reshaping of the mutant SG transcriptome with alterations that can be linked to neurodegeneration. Our data describe the molecular differences between physiological and pathological SG in ALS-FUS conditions, showing how FUS mutations impact the RNA and protein composition of these condensates.
应激颗粒（SG）是细胞保护机制的一部分，其中未翻译的信使 RNA 和 RNA 结合蛋白在细胞应激条件下被储存。由于蛋白质质量或数量的变化导致的组成变化会破坏它们的功能并改变它们的结构。这就是不同形式的肌萎缩侧索硬化症（ALS）的情况，其中已经提出了细胞质定位的突变蛋白（如 FUS[肉瘤融合]）与形成细胞毒性包含物之间存在因果关系。在这里，我们描述了神经母细胞瘤细胞中的 SG 转录组，并为这些凝聚物中的 RNA 募集定义了几个特征。我们证明，突变 FUS 的掺入强烈改变了 SG 的动力学和 RNA 含量，转而形成更无组织的、富含 AU 的 SG 转录组。此外，我们表明，突变 FUS 与其蛋白相互作用物及其靶 RNA 一起负责重塑突变 SG 转录组，这些改变可以与神经退行性变相关。我们的数据描述了 ALS-FUS 条件下生理和病理 SG 之间的分子差异，显示了 FUS 突变如何影响这些凝聚物的 RNA 和蛋白质组成。
