TY  - JOUR
AU  - Dormann, Dorothee
AU  - Madl, Tobias
AU  - Valori, Chiara F
AU  - Bentmann, Eva
AU  - Tahirovic, Sabina
AU  - Abou-Ajram, Claudia
AU  - Kremmer, Elisabeth
AU  - Ansorge, Olaf
AU  - Mackenzie, Ian R A
AU  - Neumann, Manuela
AU  - Haass, Christian
TI  - Arginine methylation next to the PY-NLS modulates Transportin binding and nuclear import of FUS.
JO  - The EMBO journal
VL  - 31
IS  - 22
SN  - 0261-4189
CY  - Hoboken, NJ [u.a.]
PB  - Wiley
M1  - DZNE-2020-03019
SP  - 4258-4275
PY  - 2012
AB  - 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.
KW  - Active Transport, Cell Nucleus
KW  - Amino Acid Sequence
KW  - Amyotrophic Lateral Sclerosis: genetics
KW  - Amyotrophic Lateral Sclerosis: metabolism
KW  - Arginine: metabolism
KW  - Cell Nucleus: metabolism
KW  - Frontotemporal Lobar Degeneration: metabolism
KW  - Gene Silencing
KW  - HeLa Cells
KW  - Humans
KW  - Karyopherins: genetics
KW  - Karyopherins: metabolism
KW  - Methylation
KW  - Molecular Sequence Data
KW  - Nuclear Localization Signals: metabolism
KW  - Proline: metabolism
KW  - Protein Binding
KW  - Protein-Arginine N-Methyltransferases: genetics
KW  - Protein-Arginine N-Methyltransferases: metabolism
KW  - RNA-Binding Protein FUS: genetics
KW  - RNA-Binding Protein FUS: metabolism
KW  - Repressor Proteins: genetics
KW  - Repressor Proteins: metabolism
KW  - Signal Transduction
KW  - Tyrosine: metabolism
KW  - Karyopherins (NLM Chemicals)
KW  - Nuclear Localization Signals (NLM Chemicals)
KW  - RNA-Binding Protein FUS (NLM Chemicals)
KW  - Repressor Proteins (NLM Chemicals)
KW  - Tyrosine (NLM Chemicals)
KW  - Arginine (NLM Chemicals)
KW  - Proline (NLM Chemicals)
KW  - PRMT1 protein, human (NLM Chemicals)
KW  - Protein-Arginine N-Methyltransferases (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:22968170
C2  - pmc:PMC3501225
DO  - DOI:10.1038/emboj.2012.261
UR  - https://pub.dzne.de/record/136697
ER  -