Mahendran Tharun Selvam, Wadsworth Gable M, Singh Anurag, Gupta Ritika, Banerjee Priya R
Department of Biological Sciences, The State University of New York at Buffalo, Buffalo, NY, USA.
Department of Physics, The State University of New York at Buffalo, Buffalo, NY, USA.
Nat Chem. 2025 Jul 2. doi: 10.1038/s41557-025-01847-3.
RNA-driven condensation plays a central role in organizing and regulating ribonucleoprotein granules within cells. Disruptions to this process-such as the aberrant aggregation of repeat-expanded RNA-are associated with numerous neurological disorders. Here we study the role of biomolecular condensates in irreversible RNA aggregation. We find that physiologically relevant and disease-associated repeat RNAs spontaneously undergo an age-dependent percolation transition inside multi-component condensates to form nanoscale clusters. Homotypic RNA clusters drive the emergence of multi-phasic condensate structures, with an RNA-rich solid core surrounded by an RNA-depleted fluid shell. The timescale of RNA clustering is determined by sequence, secondary structure and repeat length. Importantly, G3BP1, the core scaffold of stress granules, introduces heterotypic buffering to homotypic RNA-RNA interactions and prevents RNA clustering in an ATP-independent manner. Our work suggests that biomolecular condensates can act as sites for RNA aggregation and highlights the chaperone-like function of RNA-binding proteins against aberrant RNA phase transitions.
RNA驱动的凝聚在细胞内核糖核蛋白颗粒的组织和调节中起着核心作用。这一过程的破坏，如重复扩增RNA的异常聚集，与多种神经疾病相关。在这里，我们研究生物分子凝聚物在不可逆RNA聚集过程中的作用。我们发现，生理相关和疾病相关的重复RNA在多组分凝聚物中会自发经历年龄依赖性的渗流转变，形成纳米级簇。同型RNA簇驱动多相凝聚物结构的出现，即富含RNA的实心核心被RNA耗尽的流体壳包围。RNA聚类的时间尺度由序列、二级结构和重复长度决定。重要的是，应激颗粒的核心支架G3BP1为同型RNA-RNA相互作用引入异型缓冲，并以不依赖ATP的方式阻止RNA聚类。我们的工作表明，生物分子凝聚物可以作为RNA聚集的场所，并突出了RNA结合蛋白针对异常RNA相变的伴侣样功能。
