engDormann, DorotheeMadl, TobiasHaass, ChristianValori, Chiara FBentmann, EvaTahirovic, SabinaAbou-Ajram, ClaudiaKremmer, ElisabethAnsorge, OlafMackenzie, Ian R ANeumann, ManuelaArginine methylation next to the PY-NLS modulates Transportin binding and nuclear import of FUS.info:eu-repo/classification/ddc/570Active Transport, Cell NucleusAmino Acid SequenceAmyotrophic Lateral Sclerosis: geneticsAmyotrophic Lateral Sclerosis: metabolismArginine: metabolismCell Nucleus: metabolismFrontotemporal Lobar Degeneration: metabolismGene SilencingHeLa CellsHumansKaryopherins: geneticsKaryopherins: metabolismMethylationMolecular Sequence DataNuclear Localization Signals: metabolismProline: metabolismProtein BindingProtein-Arginine N-Methyltransferases: geneticsProtein-Arginine N-Methyltransferases: metabolismRNA-Binding Protein FUS: geneticsRNA-Binding Protein FUS: metabolismRepressor Proteins: geneticsRepressor Proteins: metabolismSignal TransductionTyrosine: metabolismKaryopherinsNuclear Localization SignalsRNA-Binding Protein FUSRepressor ProteinsTyrosineArginineProlinePRMT1 protein, humanProtein-Arginine N-MethyltransferasesFused 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.The EMBO journal 31(22), 4258-4275 (2012). doi:10.1038/emboj.2012.261info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionWiley2012info:eu-repo/semantics/closedAccessDEhttps://pub.dzne.de/record/136697https://pub.dzne.de/search?p=id:%22DZNE-2020-03019%22Researchersinfo:eu-repo/semantics/altIdentifier/issn/1460-2075info:eu-repo/semantics/altIdentifier/doi/10.1038/emboj.2012.261info:eu-repo/semantics/altIdentifier/pmid/pmid:22968170info:eu-repo/semantics/altIdentifier/issn/0261-4189