4.8 Article

Arginine methylation next to the PY-NLS modulates Transportin binding and nuclear import of FUS

期刊

EMBO JOURNAL
卷 31, 期 22, 页码 4258-4275

出版社

WILEY
DOI: 10.1038/emboj.2012.261

关键词

frontotemporal lobar degeneration (FTLD); fused in sarcoma (FUS); Transportin (TRN)

资金

  1. Sonderforschungsbereich Molecular Mechanisms of Neurodegeneration [SFB 596]
  2. Competence Network for Neurodegenerative Diseases (KNDD) of the Bundesministerium fur Bildung und Forschung (BMBF)
  3. Swiss National Science Foundation [31003A-132864]
  4. Robert Bosch Foundation
  5. Austrian Academy of Sciences
  6. Bavarian Ministry of Sciences, Research and the Arts in the framework of the Bavarian Molecular Biosystems Research Network
  7. German Research Foundation (DFG) [MA 5703/1-1]
  8. Elite Network of Bavaria
  9. NIHR Oxford Biomedical Research Centre
  10. Canadian Institutes of Health Research [179009, 74580]
  11. Pacific Alzheimer's Research Foundation centre [C06-01]
  12. 'Forschungsprofessur' of the Ludwig-Maximilians University
  13. Swiss National Science Foundation (SNF) [31003A_132864] Funding Source: Swiss National Science Foundation (SNF)
  14. Parkinson's UK [J-0901] Funding Source: researchfish

向作者/读者索取更多资源

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. The EMBO Journal (2012) 31, 4258-4275. doi:10.1038/emboj.2012.261; Published online 11 September 2012

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