%0 Journal Article
%A Dormann, Dorothee
%A Madl, Tobias
%A Valori, Chiara F
%A Bentmann, Eva
%A Tahirovic, Sabina
%A Abou-Ajram, Claudia
%A Kremmer, Elisabeth
%A Ansorge, Olaf
%A Mackenzie, Ian R A
%A Neumann, Manuela
%A Haass, Christian
%T Arginine methylation next to the PY-NLS modulates Transportin binding and nuclear import of FUS.
%J The EMBO journal
%V 31
%N 22
%@ 0261-4189
%C Hoboken, NJ [u.a.]
%I Wiley
%M DZNE-2020-03019
%P 4258-4275
%D 2012
%X 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.
%K Active Transport, Cell Nucleus
%K Amino Acid Sequence
%K Amyotrophic Lateral Sclerosis: genetics
%K Amyotrophic Lateral Sclerosis: metabolism
%K Arginine: metabolism
%K Cell Nucleus: metabolism
%K Frontotemporal Lobar Degeneration: metabolism
%K Gene Silencing
%K HeLa Cells
%K Humans
%K Karyopherins: genetics
%K Karyopherins: metabolism
%K Methylation
%K Molecular Sequence Data
%K Nuclear Localization Signals: metabolism
%K Proline: metabolism
%K Protein Binding
%K Protein-Arginine N-Methyltransferases: genetics
%K Protein-Arginine N-Methyltransferases: metabolism
%K RNA-Binding Protein FUS: genetics
%K RNA-Binding Protein FUS: metabolism
%K Repressor Proteins: genetics
%K Repressor Proteins: metabolism
%K Signal Transduction
%K Tyrosine: metabolism
%K Karyopherins (NLM Chemicals)
%K Nuclear Localization Signals (NLM Chemicals)
%K RNA-Binding Protein FUS (NLM Chemicals)
%K Repressor Proteins (NLM Chemicals)
%K Tyrosine (NLM Chemicals)
%K Arginine (NLM Chemicals)
%K Proline (NLM Chemicals)
%K PRMT1 protein, human (NLM Chemicals)
%K Protein-Arginine N-Methyltransferases (NLM Chemicals)
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:22968170
%2 pmc:PMC3501225
%R 10.1038/emboj.2012.261
%U https://pub.dzne.de/record/136697