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- Title
Arginine methylation next to the PY-NLS modulates Transportin binding and nuclear import of FUS.
- Authors
Dormann, Dorothee; Madl, Tobias; Valori, Chiara F; Bentmann, Eva; Tahirovic, Sabina; Abou-Ajram, Claudia; Kremmer, Elisabeth; Ansorge, Olaf; Mackenzie, Ian R A; Neumann, Manuela; Haass, Christian
- 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.
- Publication
The EMBO journal, 2012, Vol 31, Issue 22, p4258
- ISSN
1460-2075
- Publication type
Journal Article
- DOI
10.1038/emboj.2012.261