title: Arginine methylation next to the PY-NLS modulates Transportin binding and nuclear import of FUS.
abstract: 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.
authors.affiliation: Adolf-Butenandt-Institute, Biochemistry, Ludwig-Maximilians-University, Munich, Germany.
authors.forename: Dorothee
authors.initials: D
authors.lastname: Dormann
authors.forename: Tobias
authors.initials: T
authors.lastname: Madl
authors.forename: Chiara F
authors.initials: CF
authors.lastname: Valori
authors.forename: Eva
authors.initials: E
authors.lastname: Bentmann
authors.forename: Sabina
authors.initials: S
authors.lastname: Tahirovic
authors.forename: Claudia
authors.initials: C
authors.lastname: Abou-Ajram
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Kremmer
authors.forename: Olaf
authors.initials: O
authors.lastname: Ansorge
authors.forename: Ian R A
authors.initials: IR
authors.lastname: Mackenzie
authors.forename: Manuela
authors.initials: M
authors.lastname: Neumann
authors.forename: Christian
authors.initials: C
authors.lastname: Haass
mesh_terms: D021581:Active Transport, Cell Nucleus; D000595:Amino Acid Sequence; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000378:metabolism*; D001120:Arginine / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism*; D057174:Frontotemporal Lobar Degeneration / Q000378:metabolism; D020868:Gene Silencing; D006367:HeLa Cells; D006801:Humans; D028884:Karyopherins / Q000235:genetics / Q000378:metabolism*; D008745:Methylation; D008969:Molecular Sequence Data; D019913:Nuclear Localization Signals / Q000378:metabolism*; D011392:Proline / Q000378:metabolism; D011485:Protein Binding; D011484:Protein-Arginine N-Methyltransferases / Q000235:genetics / Q000378:metabolism; D034702:RNA-Binding Protein FUS / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014443:Tyrosine / Q000378:metabolism
chemical_list: D028884:Karyopherins; D019913:Nuclear Localization Signals; D034702:RNA-Binding Protein FUS; D012097:Repressor Proteins; D014443:Tyrosine; D001120:Arginine; D011392:Proline; C099988:PRMT1 protein, human; D011484:Protein-Arginine N-Methyltransferases