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

Publication date: 19 April 2018 Source:Cell, Volume 173, Issue 3 Author(s): Mario Hofweber, Saskia Hutten, Benjamin Bourgeois, Emil Spreitzer, Annika Niedner-Boblenz, Martina Schifferer, Marc-David Ruepp, Mikael Simons, Dierk Niessing, Tobias Madl, Dorothee Dormann 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. Graphical abstract Teaser Phase separation of FUS is regulated by both arginine methylation and binding to the nuclear import r...

Source: Cell - April 20, 2018 Category: Cytology Source Type: research