Long non-coding RNAs (lncRNAs) have structural and regulatory effects on RNA-binding proteins (RBPs). However, the mechanisms by which lncRNAs regulate the neurodegenerative-causative RBP like FUS protein remain poorly understood. Here, we show that knockdown of the Drosophila lncRNA hsrω causes a shift in the methylation status of human FUS from mono- (MMA) to di-methylated (DMA) arginine via upregulation of the arginine methyltransferase 5 (PRMT5, known as ART5 in flies). We found this novel regulatory role to be critical for FUS toxicity since the PRMT5-dependent dimethylation of FUS is required for its proteasomal degradation and causes a reduction of high levels of FUS. Moreover, we show that an increase of FUS causes a decline of both PRMT1 (known as ART1 in flies) and PRMT5 transcripts, leading to an accumulation of neurotoxic MMA-FUS. Therefore, overexpression of either PRMT1 or PRMT5 is able to rescue the FUS toxicity. These results highlight a novel role of lncRNAs in post-translation modification (PTM) of FUS and suggest a causal relationship between lncRNAs and dysfunctional PRMTs in the pathogenesis of FUSopathies.

中文翻译：

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lncRNAhsrω调节人FUS的精氨酸二甲基化，导致其在果蝇中的蛋白酶体降解。

长的非编码RNA（lncRNA）对RNA结合蛋白（RBP）具有结构和调节作用。但是，关于lncRNA调节FUS蛋白等神经退行性RBP的机制仍知之甚少。在这里，我们显示果蝇lncRNAhsrω的敲低导致人类FUS的甲基化状态通过精氨酸甲基转移酶5（PRMT5，在果蝇中被称为ART5）上调而从单（MMA）变为二甲基（DMA）精氨酸。 ）。我们发现这种新颖的调节作用对于FUS毒性至关重要，因为FUS依赖PRMT5的二甲基化对其蛋白酶体降解是必需的，并导致高水平FUS的降低。此外，我们显示FUS的增加会导致PRMT1（在果蝇中称为ART1）和PRMT5转录本的下降，从而导致神经毒性MMA-FUS的积累。因此，PRMT1或PRMT5的过表达能够挽救FUS毒性。这些结果突出了lncRNAs在FUS的翻译后修饰（PTM）中的新作用，并暗示了lncRNAs和功能异常的PRMTs在FUSopathies发病机理中的因果关系。