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

doi:10.1016/j.cell.2018.03.004

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

Basic and Clinical Neuroscience

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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-?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.

Original language	English
Pages (from-to)	706-719.e13
Number of pages	14
Journal	Cell
Volume	173
Issue number	3
Early online date	19 Apr 2018
DOIs	https://doi.org/10.1016/j.cell.2018.03.004
Publication status	E-pub ahead of print - 19 Apr 2018

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Phase Separation of FUS_HOFWEBER_Accepted28February2018_GREEN AAMAccepted author manuscript, 2.52 MBLicence: CC BY-NC-ND

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title = "Phase Separation of FUS Is Suppressed by Its Nuclear Import Receptor and Arginine Methylation",

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-?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.",

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

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T1 - Phase Separation of FUS Is Suppressed by Its Nuclear Import Receptor and Arginine Methylation

AU - Hofweber, Mario

AU - Hutten, Saskia

AU - Bourgeois, Benjamin

AU - Spreitzer, Emil

AU - Niedner-Boblenz, Annika

AU - Schifferer, Martina

AU - Ruepp, Marc-David

AU - Simons, Mikael

AU - Niessing, Dierk

AU - Madl, Tobias

AU - Dormann, Dorothee

PY - 2018/4/19

Y1 - 2018/4/19

N2 - 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-?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.

AB - 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-?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.

U2 - 10.1016/j.cell.2018.03.004

DO - 10.1016/j.cell.2018.03.004

M3 - Article

SN - 0092-8674

VL - 173

SP - 706-719.e13

JO - Cell

JF - Cell

IS - 3

ER -

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

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