PuSH - Publikationsserver des Helmholtz Zentrums München

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

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

EMBO J. 31, 4258-4275 (2012)
Verlagsversion Volltext DOI
Free by publisher
Open Access Green möglich sobald Postprint bei der ZB eingereicht worden ist.
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.
Weitere Metriken?
Zusatzinfos bearbeiten [➜Einloggen]
Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter 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
Zeitschrift EMBO Journal, The
Quellenangaben Band: 31, Heft: 22, Seiten: 4258-4275 Artikelnummer: , Supplement: ,
Verlag Wiley
Verlagsort Heidelberg, Germany
Begutachtungsstatus Peer reviewed