Journal article
Nuclear-Import Receptors Reverse Aberrant Phase Transitions of RNA-Binding Proteins with Prion-like Domains
Cell, v 173(3), pp 677-692
19 Apr 2018
PMID: 29677512
Featured in Collection : UN Sustainable Development Goals @ Drexel
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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•Nuclear-localization sequences (NLSs) are disaggregation signals in the cytoplasm•Nuclear-import receptors (NIRs) disaggregate NLS-bearing cargo in the cytoplasm•NIRs reverse phase separation by RNA-binding proteins with prion-like domains•NIRs rescue degeneration caused by disease-linked FUS and hnRNPA2 in vivo
Nuclear-import receptors can reverse phase separation and aggregation of proteins with prion-like domains, including FUS and TDP-43, to mitigate neurodegeneration in vivo.
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Details
- Title
- Nuclear-Import Receptors Reverse Aberrant Phase Transitions of RNA-Binding Proteins with Prion-like Domains
- Creators
- Lin Guo - University of PennsylvaniaHong Joo Kim - St. Jude Children's Research HospitalHejia Wang - University of PennsylvaniaJohn Monaghan - Children's Hospital of PittsburghFernande Freyermuth - Massachusetts General HospitalJulie C. Sung - University of PennsylvaniaKevin O’Donovan - Department of Cell and Molecular Biology, St. Jude Children’s Research Hospital, Memphis, TN 38120, USACharlotte M. Fare - University of PennsylvaniaZamia Diaz - University of PennsylvaniaNikita Singh - University of PennsylvaniaZi Chao Zhang - The University of Texas Southwestern Medical CenterMaura Coughlin - St. Jude Children's Research HospitalElizabeth A. Sweeny - University of PennsylvaniaMorgan E. DeSantis - University of PennsylvaniaMeredith E. Jackrel - University of PennsylvaniaChristopher B. Rodell - University of PennsylvaniaJason A. Burdick - University of PennsylvaniaOliver D. King - University of Massachusetts Medical SchoolAaron D. Gitler - Stanford UniversityClotilde Lagier-Tourenne - Massachusetts General HospitalUdai Bhan Pandey - Children's Hospital of PittsburghYuh Min Chook - The University of Texas Southwestern Medical CenterJ. Paul Taylor - St. Jude Children's Research HospitalJames Shorter - University of Pennsylvania
- Publication Details
- Cell, v 173(3), pp 677-692
- Publisher
- Elsevier
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- School of Biomedical Engineering, Science, and Health Systems
- Web of Science ID
- WOS:000430677400017
- Scopus ID
- 2-s2.0-85045775165
- Other Identifier
- 991019176805204721
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- Collaboration types
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Biochemistry & Molecular Biology
- Cell Biology