The lncRNA hsrω regulates arginine dimethylation of FUS to cause its proteasomal degradation in Drosophila

Abstract

The lncRNAs play structural and regulatory roles on RNA-binding proteins (RBPs). However, the mechanisms by which lncRNAs regulate the neurodegenerative-causative RBP like FUS remain poorly understood. Here, we show that knockdown of the lncRNA hsrω causes a shift in the methylation status of FUS from mono- (MMA) to di-methylated (DMA) arginine via upregulation of the argininemethyl transferases 5 (PRMT5). We found this novel regulatory role to be critical to 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 determines a decline of both PRMT 1 and 5 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.