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

Overview

Journal Cell

Publisher Cell Press

Specialty Cell Biology

Date 2018 Apr 21

PMID 29677512

Citations 244

Authors

Lin Guo

Hong Joo Kim

Hejia Wang

John Monaghan

Fernande Freyermuth

Julie C Sung

Kevin ODonovan

Charlotte M Fare

Zamia Diaz

Nikita Singh

Zi Chao Zhang

Maura Coughlin

Elizabeth A Sweeny

Morgan E DeSantis

Meredith E Jackrel

Christopher B Rodell

Jason A Burdick

Oliver D King

Aaron D Gitler

Clotilde Lagier-Tourenne

Udai Bhan Pandey

Yuh Min Chook

J Paul Taylor

James Shorter

Affiliations

Soon will be listed here.

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.

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