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

• Published in: Cell Vol. 173; no. 3; pp. 677 - 692.e20
• Main Authors: Guo, Lin, Kim, Hong Joo, Wang, Hejia, Monaghan, John, Freyermuth, Fernande, Sung, Julie C., O’Donovan, Kevin, Fare, Charlotte M., Diaz, Zamia, Singh, Nikita, Zhang, Zi Chao, Coughlin, Maura, Sweeny, Elizabeth A., DeSantis, Morgan E., Jackrel, Meredith E., Rodell, Christopher B., Burdick, Jason A., King, Oliver D., Gitler, Aaron D., Lagier-Tourenne, Clotilde, Pandey, Udai Bhan, Chook, Yuh Min, Taylor, J. Paul, Shorter, James
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 19.04.2018
• Subjects: Active Transport, Cell Nucleus; Adult; Aged; ALS; Animals; beta Karyopherins - chemistry; Cytoplasm - chemistry; disaggregase; DNA-Binding Proteins - chemistry; Drosophila melanogaster; Female; FTD; FUS; Green Fluorescent Proteins - chemistry; HEK293 Cells; HeLa Cells; hnRNPA1; Homeostasis; Humans; Karyopherin-β2; Karyopherins - chemistry; Male; Middle Aged; Molecular Chaperones - chemistry; Mutation; neurodegeneration; Neurodegenerative Diseases - pathology; Nuclear-important receptor; phase transition; Prions - chemistry; Protein Domains; Receptors, Cytoplasmic and Nuclear - chemistry; RNA-Binding Protein EWS - chemistry; RNA-Binding Proteins - chemistry; TATA-Binding Protein Associated Factors - chemistry; TDP-43; disaggregase; FUS; TDP-43; Nuclear-important receptor; FTD; ALS; neurodegeneration; phase transition; hnRNPA1; Karyopherin-β2
• ISSN: 0092-8674; 1097-4172
• 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. [Display omitted] •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.