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Cell. 2018 Apr 19;173(3):706-719.e13. doi: 10.1016/j.cell.2018.03.004.

Phase Separation of FUS Is Suppressed by Its Nuclear Import Receptor and Arginine Methylation.

Author information

1
Biomedical Center (BMC), Ludwig-Maximilians University of Munich, 82152 Planegg-Martinsried, Germany; Graduate School of Systemic Neurosciences (GSN), Ludwig-Maximilians University of Munich, 82152 Planegg-Martinsried, Germany.
2
Biomedical Center (BMC), Ludwig-Maximilians University of Munich, 82152 Planegg-Martinsried, Germany.
3
Institute of Molecular Biology & Biochemistry, Center of Molecular Medicine, Medical University of Graz, 8010 Graz, Austria.
4
Biomedical Center (BMC), Ludwig-Maximilians University of Munich, 82152 Planegg-Martinsried, Germany; Institute of Structural Biology, Helmholtz Zentrum München, German Research Center for Environmental Health, 85763 Neuherberg, Germany.
5
Institute of Neuronal Cell Biology, Technical University of Munich, 80805 Munich, Germany; German Center for Neurodegenerative Diseases (DZNE), 81377 Munich, Germany; Munich Cluster for Systems Neurology (SyNergy); 81377 Munich, Germany.
6
Department of Chemistry and Biochemistry, University of Bern, 3012 Bern, Switzerland.
7
Biomedical Center (BMC), Ludwig-Maximilians University of Munich, 82152 Planegg-Martinsried, Germany; Institute of Structural Biology, Helmholtz Zentrum München, German Research Center for Environmental Health, 85763 Neuherberg, Germany; Institute of Pharmaceutical Biotechnology, Ulm University, 89081 Ulm, Germany.
8
Biomedical Center (BMC), Ludwig-Maximilians University of Munich, 82152 Planegg-Martinsried, Germany; Graduate School of Systemic Neurosciences (GSN), Ludwig-Maximilians University of Munich, 82152 Planegg-Martinsried, Germany; Munich Cluster for Systems Neurology (SyNergy); 81377 Munich, Germany. Electronic address: dorothee.dormann@med.uni-muenchen.de.

Abstract

Cytoplasmic FUS aggregates are a pathological hallmark in a subset of patients with frontotemporal dementia (FTD) or amyotrophic lateral sclerosis (ALS). A key step that is disrupted in these patients is nuclear import of FUS mediated by the import receptor Transportin/Karyopherin-β2. In ALS-FUS patients, this is caused by mutations in the nuclear localization signal (NLS) of FUS that weaken Transportin binding. In FTD-FUS patients, Transportin is aggregated, and post-translational arginine methylation, which regulates the FUS-Transportin interaction, is lost. Here, we show that Transportin and arginine methylation have a crucial function beyond nuclear import-namely to suppress RGG/RG-driven phase separation and stress granule association of FUS. ALS-associated FUS-NLS mutations weaken the chaperone activity of Transportin and loss of FUS arginine methylation, as seen in FTD-FUS, promote phase separation, and stress granule partitioning of FUS. Our findings reveal two regulatory mechanisms of liquid-phase homeostasis that are disrupted in FUS-associated neurodegeneration.

KEYWORDS:

ALS; FTD; Karyopherin-β2 (Kapβ2); Transportin (TNPO1); arginine methylation; fused in sarcoma (FUS); neurodegeneration; nuclear import; phase separation; stress granules

PMID:
29677514
DOI:
10.1016/j.cell.2018.03.004

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