136697 20240619104245.0 10.1038/emboj.2012.261 doi pmid:22968170 pmid pmc:PMC3501225 pmc 0261-4189 ISSN 1460-2075 ISSN altmetric:43347789 altmetric DZNE-2020-03019 English 570 Dormann, Dorothee P:(DE-2719)9000059 0 First author Arginine methylation next to the PY-NLS modulates Transportin binding and nuclear import of FUS. Hoboken, NJ [u.a.] 2012 Wiley online Crossref Wiley 2012-09-11 print Crossref Wiley 2012-11-14 article DRIVER Output Types/Journal article DataCite Journal Article journal journal PUB:(DE-HGF)16 1718786500_8364 PUB:(DE-HGF) ARTICLE BibTeX JOURNAL_ARTICLE ORCID Journal Article 0 EndNote 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. 344 - Clinical and Health Care Research (POF3-344) G:(DE-HGF)POF3-344 POF3-344 POF III 0 2015-09-01 Crossref http://doi.wiley.com/10.1002/tdm_license_1.1 Dataset connected to CrossRef, PubMed, Karyopherins NLM Chemicals Nuclear Localization Signals NLM Chemicals RNA-Binding Protein FUS NLM Chemicals Repressor Proteins NLM Chemicals Tyrosine 42HK56048U NLM Chemicals Arginine 94ZLA3W45F NLM Chemicals Proline 9DLQ4CIU6V NLM Chemicals PRMT1 protein, human EC 2.1.1.319 NLM Chemicals Protein-Arginine N-Methyltransferases EC 2.1.1.319 NLM Chemicals Active Transport, Cell Nucleus MeSH Amino Acid Sequence MeSH Amyotrophic Lateral Sclerosis: genetics MeSH Amyotrophic Lateral Sclerosis: metabolism MeSH Arginine: metabolism MeSH Cell Nucleus: metabolism MeSH Frontotemporal Lobar Degeneration: metabolism MeSH Gene Silencing MeSH HeLa Cells MeSH Humans MeSH Karyopherins: genetics MeSH Karyopherins: metabolism MeSH Methylation MeSH Molecular Sequence Data MeSH Nuclear Localization Signals: metabolism MeSH Proline: metabolism MeSH Protein Binding MeSH Protein-Arginine N-Methyltransferases: genetics MeSH Protein-Arginine N-Methyltransferases: metabolism MeSH RNA-Binding Protein FUS: genetics MeSH RNA-Binding Protein FUS: metabolism MeSH Repressor Proteins: genetics MeSH Repressor Proteins: metabolism MeSH Signal Transduction MeSH Tyrosine: metabolism MeSH Madl, Tobias P:(DE-HGF)0 1 Valori, Chiara F P:(DE-2719)2810632 2 Bentmann, Eva P:(DE-HGF)0 3 Tahirovic, Sabina P:(DE-HGF)0 4 Abou-Ajram, Claudia P:(DE-HGF)0 5 Kremmer, Elisabeth P:(DE-HGF)0 6 Ansorge, Olaf P:(DE-HGF)0 7 Mackenzie, Ian R A P:(DE-HGF)0 8 Neumann, Manuela P:(DE-2719)2810592 9 Haass, Christian P:(DE-HGF)0 10 10.1038/emboj.2012.261 : Wiley, 2012-09-11 22 4258-4275 journal-article Crossref The EMBO Journal 31 2012 0261-4189 10.1038/emboj.2012.261 Vol. 31, no. 22, p. 4258 - 4275 PERI:(DE-600)1467419-1 22 31:22<4258 - 4275 4258-4275 The EMBO journal 31 2012 0261-4189 Pubmed Central http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3501225 http://pub.dzne.de/record/136697/files/DZNE-2020-03019_Restricted.pdf http://pub.dzne.de/record/136697/files/DZNE-2020-03019_Restricted.pdf?subformat=pdfa pdfa VDB oai:pub.dzne.de:136697 Deutsches Zentrum für Neurodegenerative Erkrankungen I:(DE-588)1065079516 DZNE 0 P:(DE-2719)9000059 Deutsches Zentrum für Neurodegenerative Erkrankungen I:(DE-588)1065079516 DZNE 2 P:(DE-2719)2810632 Deutsches Zentrum für Neurodegenerative Erkrankungen I:(DE-588)1065079516 DZNE 9 P:(DE-2719)2810592 DE-HGF Gesundheit Erkrankungen des Nervensystems G:(DE-HGF)POF3-340 G:(DE-HGF)POF3-344 G:(DE-HGF)POF3 G:(DE-HGF)POF3-300 G:(DE-HGF)POF Clinical and Health Care Research 0 2012 JCR 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