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

Lin Guo, Hong Joo Kim, Hejia Wang, John Monaghan, Fernande Freyermuth, Julie C. Sung, Kevin O'Donovan, 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-TourenneUdai Bhan Pandey, Yuh Min Chook, J. Paul Taylor, James Shorter

Research output: Contribution to journalArticlepeer-review

259 Scopus citations


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. 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.

Original languageEnglish
Pages (from-to)677-692.e20
Issue number3
StatePublished - Apr 19 2018


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


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