Open AccessThe lncRNA hsrω regulates arginine dimethylation of FUS to cause its proteasomal degradation in Drosophila
Author(s) -
Luca Lo Piccolo,
Hideki Mochizuki,
Yoshitaka Nagai
Publication year - 2019
Publication title -
journal of cell science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.384
H-Index - 278
eISSN - 1477-9137
pISSN - 0021-9533
DOI - 10.1242/jcs.236836
Subject(s) - biology , degradation (telecommunications) , arginine , drosophila (subgenus) , microbiology and biotechnology , genetics , amino acid , gene , telecommunications , computer science
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.