期刊
JOURNAL OF CELL SCIENCE
卷 132, 期 20, 页码 -出版社
COMPANY BIOLOGISTS LTD
DOI: 10.1242/jcs.236836
关键词
lncRNAs; Arginine dimethylation; Post-translation modification; RBP homeostasis; FUS toxicity; FUS cellular localisation; Neurodegeneration; Drosophila
类别
资金
- Ministry of Education, Culture, Sports, Science and Technology, Japan [17H05699]
- Health and Labour Sciences Research Grant for Research on Development of New Drugs from the Ministry of Health, Labour and Welfare, Japan [H24-Soyaku-Sogo-002]
- grants for Practical Research Projects for Rare/Intractable Diseases from Japan Agency for Medical Research and Development, Japan [JP16Aek0109018, JP19ek0109222, JP19ek0109316]
- Intramural Research Grants for Neurological and Psychiatric Disorders from the National Center of Neurology and Psychiatry [27-7, 27-9]
- IBC Grant from the Japan Amyotrophic Lateral Sclerosis Association
- Grants-in-Aid for Scientific Research [17H05699] Funding Source: KAKEN
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 hsr omega 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.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据