Journal Article

DZNE-2020-03019

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Arginine methylation next to the PY-NLS modulates Transportin binding and nuclear import of FUS.

Dormann, D. (First author)DZNE* ; Madl, T. ; Valori, C. F.DZNE* ; Bentmann, E. ; Tahirovic, S. ; Abou-Ajram, C. ; Kremmer, E. ; Ansorge, O. ; Mackenzie, I. R. A. ; Neumann, M.DZNE* ; Haass, C.

2012
Wiley Hoboken, NJ [u.a.]

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Please use a persistent id in citations: doi:10.1038/emboj.2012.261

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.

Keyword(s): Active Transport, Cell Nucleus (MeSH) ; Amino Acid Sequence (MeSH) ; Amyotrophic Lateral Sclerosis: genetics (MeSH) ; Amyotrophic Lateral Sclerosis: metabolism (MeSH) ; Arginine: metabolism (MeSH) ; Cell Nucleus: metabolism (MeSH) ; Frontotemporal Lobar Degeneration: metabolism (MeSH) ; Gene Silencing (MeSH) ; HeLa Cells (MeSH) ; Humans (MeSH) ; Karyopherins: genetics (MeSH) ; Karyopherins: metabolism (MeSH) ; Methylation (MeSH) ; Molecular Sequence Data (MeSH) ; Nuclear Localization Signals: metabolism (MeSH) ; Proline: metabolism (MeSH) ; Protein Binding (MeSH) ; Protein-Arginine N-Methyltransferases: genetics (MeSH) ; Protein-Arginine N-Methyltransferases: metabolism (MeSH) ; RNA-Binding Protein FUS: genetics (MeSH) ; RNA-Binding Protein FUS: metabolism (MeSH) ; Repressor Proteins: genetics (MeSH) ; Repressor Proteins: metabolism (MeSH) ; Signal Transduction (MeSH) ; Tyrosine: metabolism (MeSH) ; Karyopherins ; Nuclear Localization Signals ; RNA-Binding Protein FUS ; Repressor Proteins ; Tyrosine ; Arginine ; Proline ; PRMT1 protein, human ; Protein-Arginine N-Methyltransferases

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Contributing Institute(s):

1. Molecular Neuropathology of Neurodegenerative Diseases (AG Neumann)

Research Program(s):

1. 344 - Clinical and Health Care Research (POF3-344) (POF3-344)

Appears in the scientific report 2012

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Database coverage:
; BIOSIS Previews ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; Ebsco Academic Search ; IF >= 10 ; JCR ; NCBI Molecular Biology Database ; PubMed Central ; SCOPUS ; Science Citation Index ; Science Citation Index Expanded ; Web of Science Core Collection

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