17 Dormann, Dorothee Madl, Tobias Valori, Chiara F Bentmann, Eva Tahirovic, Sabina Abou-Ajram, Claudia Kremmer, Elisabeth Ansorge, Olaf Mackenzie, Ian R A Neumann, Manuela Haass, Christian AG Neumann The EMBO journal The EMBO journal Wiley Hoboken, NJ [u.a.] 0261-4189 10.1038/emboj.2012.261 English 4258-4275 22 31 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. PUB:(DE-HGF)16, ; 0, ; Active Transport, Cell Nucleus Amino Acid Sequence Amyotrophic Lateral Sclerosis: genetics Amyotrophic Lateral Sclerosis: metabolism Arginine: metabolism Cell Nucleus: metabolism Frontotemporal Lobar Degeneration: metabolism Gene Silencing HeLa Cells Humans Karyopherins: genetics Karyopherins: metabolism Methylation Molecular Sequence Data Nuclear Localization Signals: metabolism Proline: metabolism Protein Binding Protein-Arginine N-Methyltransferases: genetics Protein-Arginine N-Methyltransferases: metabolism RNA-Binding Protein FUS: genetics RNA-Binding Protein FUS: metabolism Repressor Proteins: genetics Repressor Proteins: metabolism Signal Transduction Tyrosine: metabolism Karyopherins Nuclear Localization Signals RNA-Binding Protein FUS Repressor Proteins Tyrosine Arginine Proline PRMT1 protein, human Protein-Arginine N-Methyltransferases Journal Article 2012 DZNE-2020-03019 2012 pmc:PMC3501225 pmid:22968170 https://pub.dzne.de/record/136697 https://doi.org/10.1038/emboj.2012.261