Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
Dormann, D; Madl, T; Valori, CF; Bentmann, E; Tahirovic, S; Abou-Ajram, C; Kremmer, E; Ansorge, O; Mackenzie, IR; Neumann, M; Haass, C.
Arginine methylation next to the PY-NLS modulates Transportin binding and nuclear import of FUS.
EMBO J. 2012; 31(22): 4258-4275.
Doi: 10.1038/emboj.2012.261
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- Co-Autor*innen der Med Uni Graz
- Madl Tobias
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- 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.
- Find related publications in this database (using NLM MeSH Indexing)
- 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
- Find related publications in this database (Keywords)
- frontotemporal lobar degeneration (FTLD)
- fused in sarcoma (FUS)
- Transportin (TRN)