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Open Access Green as soon as Postprint is submitted to ZB.
Arginine methylation next to the PY-NLS modulates transportin binding and nuclear import of FUS.
EMBO J. 31, 4258-4275 (2012)
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.
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Publication type
Article: Journal article
Document type
Scientific Article
Keywords
amyotrophic lateral sclerosis (ALS); arginine methylation; frontotemporal lobar degeneration (FTLD); fused in sarcoma (FUS); Transportin (TRN)
ISSN (print) / ISBN
0261-4189
e-ISSN
1460-2075
Journal
EMBO Journal, The
Quellenangaben
Volume: 31,
Issue: 22,
Pages: 4258-4275
Publisher
Wiley
Publishing Place
Heidelberg, Germany
Non-patent literature
Publications
Reviewing status
Peer reviewed