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

Hofweber, Mario; Hutten, Saskia; Bourgeois, Benjamin; Spreitzer, Emil; Niedner-Boblenz, Annika; Schifferer, Martina; Ruepp, Marc-David; Simons, Mikael; Niessing, Dierk; Madl, Tobias; Dormann, Dorothee (2018): Phase Separation of FUS Is Suppressed by Its Nuclear Import Receptor and Arginine Methylation. In: Cell, Vol. 173, No. 3: pp. 706-719

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-beta 2. 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.

• Item Type: Journal article
• Faculties: Medicine
• Research Centers: Graduate School of Systemic Neurosciences (GSN)
• Subjects: 600 Technology > 610 Medicine and health; 500 Science > 500 Science
• ISSN: 0092-8674
• Language: English