EWSR1 结合 40S 核糖体亚基并抑制翻译以维持内质网稳态
EWSR1 associates with the 40S ribosomal subunit and represses translation to maintain endoplasmic reticulum homeostasis
EWSR1 在癌细胞中作为选择性翻译抑制因子，靶向脂质代谢与内质网稳态相关 mRNA。EWSR1 缺失会破坏内质网形态并损害未折叠蛋白反应（UPRER）的激活。机制上，EWSR1 结合靶 mRNA 后抑制其翻译，其包含两个 RGG 盒的保守区域参与同 40S 核糖体亚基的结合。该研究发表于 Nucleic Acids Research，提出 EWSR1 在转录后基因调控中的新作用，并提示其翻译活性异常可能与 FET 相关疾病的发病机制有关。
来源：Nucleic Acids Research · doi.org
FET family proteins (FUS, EWSR1, and TAF15) have garnered significant attention due to their involvement in oncogenic fusions and mutations in various cancers and neurodegenerative disorders. Although these highly conserved RNA-binding proteins are widely described as multifunctional regulators of gene expression, their precise molecular functions remain incompletely understood. Here, we uncover a previously unrecognized role for EWSR1 as a selective translational repressor in cancer cells. EWSR1 specifically targets mRNAs involved in lipid metabolism and endoplasmic reticulum (ER) homeostasis. Loss of EWSR1 disrupts ER morphology and impairs activation of the unfolded protein response of the ER (UPRER). Mechanistically, EWSR1 represses translation upon association with target mRNAs, and its conserved region spanning two arginine–glycine–glycine (RGG) boxes contributes to association with the 40S ribosomal subunit. These findings define a novel role for EWSR1 in post-transcriptional gene regulation and suggest that perturbations in its translational activity may underlie the pathogenesis of FET-associated diseases.