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Cytoplasmic granule formation by FUS‐R495X is attributable to arginine methylation in all Gly‐rich, RGG1 and RGG2 domains
Genes to Cells ( IF 1.3 ) Pub Date : 2021-01-07 , DOI: 10.1111/gtc.12827
Daiki Kawahara 1 , Toshiharu Suzuki 1 , Tadashi Nakaya 2
Affiliation  

Many mutations in the fused in sarcoma (FUS) gene have been identified as genetic causative factors of amyotrophic lateral sclerosis (ALS). As a certain number of mutants form aberrant cytoplasmic granules under specific conditions, granule forming ability of FUS is believed to be linked to the pathogenesis of ALS. However, molecular mechanisms underlying this property remain unclear. An ALS‐linked FUS mutant, R495X, shows extensive cytoplasmic localization and forms granules in neurons. In the present study, using R495X domain deletion constructs, we showed that deletion of any of Gly‐rich, RGG1 or RGG2 significantly suppressed granule formation. Furthermore, when neurons expressing EGFP‐R495X were treated with an arginine methylation inhibitor, the number of cells displaying R495X granules was significantly reduced. When FLAG‐tagged arginine N‐methyltransferase 8 (PRMT8) was co‐expressed with EGFP‐R495X to facilitate its methylation, the number of cells with granules was significantly increased. Collectively, these findings suggest that cytoplasmic granule formation by R495X is attributable to the arginine methylation in all Gly‐rich, RGG1 and RGG2 domains.

中文翻译:

FUS-R495X形成的细胞质颗粒可归因于所有富含Gly,RGG1和RGG2域的精氨酸甲基化

肉瘤融合(FUS)基因中的许多突变已被确定为肌萎缩性侧索硬化症(ALS)的遗传病因。由于一定数量的突变体在特定条件下形成异常的细胞质颗粒,因此认为FUS的颗粒形成能力与ALS的发病机理有关。但是,尚不清楚该特性的分子机制。ALS连锁的FUS突变体R495X显示出广泛的细胞质定位,并在神经元中形成颗粒。在本研究中,我们使用R495X域缺失构建体显示,富含Gly,RGG1或RGG2的任何缺失均可显着抑制颗粒形成。此外,当用精氨酸甲基化抑制剂处理表达EGFP-R495X的神经元时,展示R495X颗粒的细胞数量显着减少。当将带有FLAG标签的精氨酸N-甲基转移酶8(PRMT8)与EGFP-R495X共表达以促进其甲基化时,带有颗粒的细胞数量显着增加。总的来说,这些发现表明,R495X形成的细胞质颗粒可归因于所有富含Gly,RGG1和RGG2结构域中的精氨酸甲基化。
更新日期:2021-03-08
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