TY - JOUR
T1 - Nuclear-Import Receptors Reverse Aberrant Phase Transitions of RNA-Binding Proteins with Prion-like Domains
AU - Guo, Lin
AU - Kim, Hong Joo
AU - Wang, Hejia
AU - Monaghan, John
AU - Freyermuth, Fernande
AU - Sung, Julie C.
AU - O'Donovan, Kevin
AU - Fare, Charlotte M.
AU - Diaz, Zamia
AU - Singh, Nikita
AU - Zhang, Zi Chao
AU - Coughlin, Maura
AU - Sweeny, Elizabeth A.
AU - DeSantis, Morgan E.
AU - Jackrel, Meredith E.
AU - Rodell, Christopher B.
AU - Burdick, Jason A.
AU - King, Oliver D.
AU - Gitler, Aaron D.
AU - Lagier-Tourenne, Clotilde
AU - Pandey, Udai Bhan
AU - Chook, Yuh Min
AU - Taylor, J. Paul
AU - Shorter, James
N1 - Publisher Copyright:
© 2018 Elsevier Inc.
PY - 2018/4/19
Y1 - 2018/4/19
N2 - 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.
AB - 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.
KW - ALS
KW - FTD
KW - FUS
KW - Karyopherin-β2
KW - Nuclear-important receptor
KW - TDP-43
KW - disaggregase
KW - hnRNPA1
KW - neurodegeneration
KW - phase transition
UR - http://www.scopus.com/inward/record.url?scp=85045775165&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85045775165&partnerID=8YFLogxK
U2 - 10.1016/j.cell.2018.03.002
DO - 10.1016/j.cell.2018.03.002
M3 - Article
C2 - 29677512
AN - SCOPUS:85045775165
SN - 0092-8674
VL - 173
SP - 677-692.e20
JO - Cell
JF - Cell
IS - 3
ER -