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Nuclear-Import Receptors Reverse Aberrant Phase Transitions of RNA-Binding Proteins with Prion-like Domains. Cell 2018 Apr 19;173(3):677-692.e20

Date

04/21/2018

Pubmed ID

29677512

Pubmed Central ID

PMC5911940

DOI

10.1016/j.cell.2018.03.002

Scopus ID

2-s2.0-85045775165 (requires institutional sign-in at Scopus site)   321 Citations

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.

Author List

Guo L, Kim HJ, Wang H, Monaghan J, Freyermuth F, Sung JC, O'Donovan K, Fare CM, Diaz Z, Singh N, Zhang ZC, Coughlin M, Sweeny EA, DeSantis ME, Jackrel ME, Rodell CB, Burdick JA, King OD, Gitler AD, Lagier-Tourenne C, Pandey UB, Chook YM, Taylor JP, Shorter J

Author

Elizabeth Sweeny PhD Assistant Professor in the Biochemistry department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Active Transport, Cell Nucleus
Adult
Aged
Animals
Cytoplasm
DNA-Binding Proteins
Drosophila melanogaster
Female
Green Fluorescent Proteins
HEK293 Cells
HeLa Cells
Homeostasis
Humans
Karyopherins
Male
Middle Aged
Molecular Chaperones
Mutation
Neurodegenerative Diseases
Prions
Protein Domains
RNA-Binding Protein EWS
RNA-Binding Proteins
Receptors, Cytoplasmic and Nuclear
TATA-Binding Protein Associated Factors
beta Karyopherins