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

Mario Hofweber, Saskia Hutten, Benjamin Bourgeois, Emil Spreitzer, Annika Niedner-Boblenz, Martina Schifferer, Marc David Ruepp, Mikael Simons, Dierk Niessing, Tobias Madl, Dorothee Dormann

Research output: Contribution to journalArticlepeer-review

426 Scopus citations


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. Phase separation of FUS is regulated by both arginine methylation and binding to the nuclear import receptor Transportin/Karyopherin-β2, and this control can be compromised in the neurodegenerative diseases FTD and ALS.

Original languageEnglish
Pages (from-to)706-719.e13
Issue number3
StatePublished - 19 Apr 2018
Externally publishedYes


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


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