The cooperative binding of TDP-43 to GU-rich RNA repeats antagonizes TDP-43 aggregation.
The cooperative binding of TDP-43 to GU-rich RNA repeats antagonizes TDP-43 aggregation.
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DOI：
10.7554/elife.67605
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发表时间：
2021-09-07
期刊：
影响因子：
7.7
通讯作者：
Bouhss A
中科院分区：
文献类型：
--
作者：
Rengifo-Gonzalez JC;El Hage K;Clément MJ;Steiner E;Joshi V;Craveur P;Durand D;Pastré D;Bouhss A
TDP-43是一种核RNA结合蛋白，在两种主要的神经退行性疾病ALS和FTLD中形成神经元胞质包涵体。虽然TDP-43通过其结构化的N-末端和固有无序的C-末端结构域的自组装已被广泛研究，但mRNA保持TDP-43在细胞核中溶解度的机制尚未得到解决。在这里，我们证明了TDP-43的串联RNA识别基序通过分子间相互作用以合作的方式与长的GU重复序列结合。此外，使用协同性受损的突变体，我们发现TDP-43与mRNA的协同结合可能是维持TDP-43在细胞核中的溶解度和TDP-43在细胞质应激颗粒中的溶解度的关键。我们预期，TDP-43在mRNA上的高阶组装的知识可以阐明其在内含子加工中的作用，并提供干扰TDP-43的胞质聚集的手段。
TDP-43 is a nuclear RNA-binding protein that forms neuronal cytoplasmic inclusions in two major neurodegenerative diseases, ALS and FTLD. While the self-assembly of TDP-43 by its structured N-terminal and intrinsically disordered C-terminal domains has been widely studied, the mechanism by which mRNA preserves TDP-43 solubility in the nucleus has not been addressed. Here, we demonstrate that tandem RNA recognition motifs of TDP-43 bind to long GU-repeats in a cooperative manner through intermolecular interactions. Moreover, using mutants whose cooperativity is impaired, we found that the cooperative binding of TDP-43 to mRNA may be critical to maintain the solubility of TDP-43 in the nucleus and the miscibility of TDP-43 in cytoplasmic stress granules. We anticipate that the knowledge of a higher order assembly of TDP-43 on mRNA may clarify its role in intron processing and provide a means of interfering with the cytoplasmic aggregation of TDP-43.