RBM45 homo-oligomerization mediates association with ALS-linked proteins and stress granules.
RBM45 homo-oligomerization mediates association with ALS-linked proteins and stress granules.
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DOI：
10.1038/srep14262
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发表时间：
2015-09-22
影响因子：
4.6
通讯作者：
Bowser R
中科院分区：
文献类型：
--
作者：
Li Y;Collins M;Geiser R;Bakkar N;Riascos D;Bowser R
RNA结合蛋白的聚集是肌萎缩侧索硬化症（ALS）和额颞叶变性（FTLD）的病理特征。RBM45是一种RNA结合蛋白，在ALS和FTLD患者的神经元和神经胶质细胞中会形成细胞质内包涵体。为探究RBM45在ALS和FTLD中的作用，我们研究了该蛋白的结构域对其功能、亚细胞定位以及与自身和ALS相关蛋白相互作用的影响。我们发现，RBM45可形成同源寡聚体，并在细胞核内与ALS相关蛋白TDP - 43和FUS存在物理性结合。RBM45的核定位由位于C端的双分型核定位序列（NLS）介导。缺乏功能性NLS的RBM45突变体在细胞质中积累，并形成TDP - 43阳性的应激颗粒。此外，我们鉴定出一种新的结构元件，称为同源寡聚体组装（HOA）结构域，该结构域在不同物种间高度保守，可促进RBM45的同源寡聚化。无法形成同源寡聚体的RBM45突变体与ALS相关蛋白的结合显著减少，且较少被纳入应激颗粒。这些结果表明，RMB45可能以同源寡聚体的形式发挥作用，其寡聚化与ALS/FTLD中RNA结合蛋白的聚集有关。
The aggregation of RNA-binding proteins is a pathological hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). RBM45 is an RNA-binding protein that forms cytoplasmic inclusions in neurons and glia in ALS and FTLD. To explore the role of RBM45 in ALS and FTLD, we examined the contribution of the protein’s domains to its function, subcellular localization, and interaction with itself and ALS-linked proteins. We find that RBM45 forms homo-oligomers and physically associates with the ALS-linked proteins TDP-43 and FUS in the nucleus. Nuclear localization of RBM45 is mediated by a bipartite nuclear-localization sequence (NLS) located at the C-terminus. RBM45 mutants that lack a functional NLS accumulate in the cytoplasm and form TDP-43 positive stress granules. Moreover, we identify a novel structural element, termed the homo-oligomer assembly (HOA) domain, that is highly conserved across species and promote homo-oligomerization of RBM45. RBM45 mutants that fail to form homo-oligomers exhibit significantly reduced association with ALS-linked proteins and inclusion into stress granules. These results show that RMB45 may function as a homo-oligomer and that its oligomerization contributes to ALS/FTLD RNA-binding protein aggregation.