Darovic Simona, Prpar Mihevc Sonja, Župunski Vera, Gunčar Gregor, Štalekar Maja, Lee Youn-Bok, Shaw Christopher E, Rogelj Boris
Jožef Stefan Institute, Department of Biotechnology, Jamova 39, Ljubljana 1000, Slovenia.
Faculty of Chemistry and Chemical Technology, University of Ljubljana, Ljubljana 1000, Slovenia.
J Cell Sci. 2015 Nov 15;128(22):4151-9. doi: 10.1242/jcs.176602. Epub 2015 Sep 24.
Aberrant cytoplasmic aggregation of FUS, which is caused by mutations primarily in the C-terminal nuclear localisation signal, is associated with 3% of cases of familial amyotrophic lateral sclerosis (ALS). FUS aggregates are also pathognomonic for 10% of all frontotemporal lobar degeneration (FTLD) cases; however, these cases are not associated with mutations in the gene encoding FUS. This suggests that there are differences in the mechanisms that drive inclusion formation of FUS in ALS and FTLD. Here, we show that the C-terminal tyrosine residue at position 526 of FUS is crucial for normal nuclear import. This tyrosine is subjected to phosphorylation, which reduces interaction with transportin 1 and might consequentially affect the transport of FUS into the nucleus. Furthermore, we show that this phosphorylation can occur through the activity of the Src family of kinases. Our study implicates phosphorylation as an additional mechanism by which nuclear transport of FUS might be regulated and potentially perturbed in ALS and FTLD.
FUS的异常细胞质聚集主要由C端核定位信号的突变引起，与3%的家族性肌萎缩侧索硬化症（ALS）病例相关。FUS聚集体在所有额颞叶痴呆（FTLD）病例中也具有病理诊断意义；然而，这些病例与编码FUS的基因突变无关。这表明在ALS和FTLD中驱动FUS包涵体形成的机制存在差异。在这里，我们表明FUS第526位的C端酪氨酸残基对于正常的核输入至关重要。该酪氨酸会发生磷酸化，这会减少与转运蛋白1的相互作用，并可能进而影响FUS进入细胞核的运输。此外，我们表明这种磷酸化可以通过Src激酶家族的活性发生。我们的研究表明磷酸化是一种额外的机制，通过该机制FUS的核运输可能在ALS和FTLD中受到调节并可能受到干扰。
