Adolf-Butenandt-Institute, Biochemistry, Ludwig-Maximilians-University, Munich, Germany.
EMBO J. 2012 Nov 14;31(22):4258-75. doi: 10.1038/emboj.2012.261. Epub 2012 Sep 11.
Fused in sarcoma (FUS) is a nuclear protein that carries a proline-tyrosine nuclear localization signal (PY-NLS) and is imported into the nucleus via Transportin (TRN). Defects in nuclear import of FUS have been implicated in neurodegeneration, since mutations in the PY-NLS of FUS cause amyotrophic lateral sclerosis (ALS). Moreover, FUS is deposited in the cytosol in a subset of frontotemporal lobar degeneration (FTLD) patients. Here, we show that arginine methylation modulates nuclear import of FUS via a novel TRN-binding epitope. Chemical or genetic inhibition of arginine methylation restores TRN-mediated nuclear import of ALS-associated FUS mutants. The unmethylated arginine-glycine-glycine domain preceding the PY-NLS interacts with TRN and arginine methylation in this domain reduces TRN binding. Inclusions in ALS-FUS patients contain methylated FUS, while inclusions in FTLD-FUS patients are not methylated. Together with recent findings that FUS co-aggregates with two related proteins of the FET family and TRN in FTLD-FUS but not in ALS-FUS, our study provides evidence that these two diseases may be initiated by distinct pathomechanisms and implicates alterations in arginine methylation in pathogenesis.
融合肉瘤（FUS）是一种核蛋白，带有脯氨酸-酪氨酸核定位信号（PY-NLS），并通过转运蛋白（TRN）被导入细胞核。FUS 的核内输入缺陷与神经退行性变有关，因为 FUS 的 PY-NLS 突变会导致肌萎缩侧索硬化症（ALS）。此外，FUS 在一部分额颞叶痴呆（FTLD）患者的细胞质中沉积。在这里，我们表明精氨酸甲基化通过一个新的 TRN 结合表位来调节 FUS 的核内输入。精氨酸甲基化的化学或遗传抑制可恢复与 ALS 相关的 FUS 突变体的 TRN 介导的核内输入。PY-NLS 前的未甲基化精氨酸-甘氨酸-甘氨酸结构域与 TRN 相互作用，并且该结构域中的精氨酸甲基化会降低 TRN 结合。ALS-FUS 患者的包涵体中含有甲基化的 FUS，而 FTLD-FUS 患者的包涵体中没有甲基化。结合最近的发现，即 FUS 在 FTLD-FUS 中与 FET 家族的两个相关蛋白和 TRN 共同聚集，但在 ALS-FUS 中则没有，我们的研究提供了证据，表明这两种疾病可能由不同的发病机制引起，并暗示精氨酸甲基化的改变在发病机制中起作用。
