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

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


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

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


  • DNA-Binding Proteins
  • EWSR1 protein, human
  • Karyopherins
  • Molecular Chaperones
  • Prions
  • RNA-Binding Protein EWS
  • RNA-Binding Proteins
  • Receptors, Cytoplasmic and Nuclear
  • TAF15 protein, human
  • TARDBP protein, human
  • TATA-Binding Protein Associated Factors
  • TNPO1 protein, human
  • beta Karyopherins
  • Green Fluorescent Proteins