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Cell. 2018 Apr 19;173(3):677-692.e20. doi: 10.1016/j.cell.2018.03.002.

Nuclear-Import Receptors Reverse Aberrant Phase Transitions of RNA-Binding Proteins with Prion-like Domains.

Author information

1
Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
2
Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN 38120, USA.
3
Department of Pediatrics, Child Neurology and Neurobiology, Children's Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, PA 15224, USA.
4
Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA; Broad Institute of Harvard University and MIT, Cambridge, MA 02142, USA.
5
Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Institute of Life Sciences, Southeast University, Nanjing, 210096 Jiangsu, China.
6
Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104, USA.
7
Department of Neurology, University of Massachusetts Medical School, Worcester, MA 01655, USA.
8
Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA.
9
Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
10
Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN 38120, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA. Electronic address: jpaul.taylor@stjude.org.
11
Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: jshorter@pennmedicine.upenn.edu.

Abstract

RNA-binding proteins (RBPs) with prion-like domains (PrLDs) phase transition to functional liquids, which can mature into aberrant hydrogels composed of pathological fibrils that underpin fatal neurodegenerative disorders. Several nuclear RBPs with PrLDs, including TDP-43, FUS, hnRNPA1, and hnRNPA2, mislocalize to cytoplasmic inclusions in neurodegenerative disorders, and mutations in their PrLDs can accelerate fibrillization and cause disease. Here, we establish that nuclear-import receptors (NIRs) specifically chaperone and potently disaggregate wild-type and disease-linked RBPs bearing a NLS. Karyopherin-β2 (also called Transportin-1) engages PY-NLSs to inhibit and reverse FUS, TAF15, EWSR1, hnRNPA1, and hnRNPA2 fibrillization, whereas Importin-α plus Karyopherin-β1 prevent and reverse TDP-43 fibrillization. Remarkably, Karyopherin-β2 dissolves phase-separated liquids and aberrant fibrillar hydrogels formed by FUS and hnRNPA1. In vivo, Karyopherin-β2 prevents RBPs with PY-NLSs accumulating in stress granules, restores nuclear RBP localization and function, and rescues degeneration caused by disease-linked FUS and hnRNPA2. Thus, NIRs therapeutically restore RBP homeostasis and mitigate neurodegeneration.

KEYWORDS:

ALS; FTD; FUS; Karyopherin-β2; Nuclear-important receptor; TDP-43; disaggregase; hnRNPA1; neurodegeneration; phase transition

PMID:
29677512
PMCID:
PMC5911940
[Available on 2019-04-19]
DOI:
10.1016/j.cell.2018.03.002
[Indexed for MEDLINE]

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