| Affiliation: | 1. Adolf‐Butenandt‐Institute, Biochemistry, Ludwig‐Maximilians‐University, , Munich, Germany;2. DZNE—German Center for Neurodegenerative Diseases, , Munich, Germany;3. Institute of Molecular Immunology, Helmholtz Zentrum München, , Munich, Germany;4. Department of Neuropathology, John Radcliffe Hospital, , Oxford, UK;5. Department of Pathology, Vancouver General Hospital, , Vancouver, Canada;6. Institute of Neuropathology, University Hospital Zurich, , Zurich, Switzerland;7. DZNE—German Center for Neurodegenerative Diseases, , Tübingen, Germany;8. Department of Neuropathology, University of Tübingen, , Tübingen, Germany;9. Munich Cluster for Systems Neurology (SyNergy), , Munich, Germany |
| 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. |
