Guo, L., Kim, H.J., Wang, H., Monaghan, J., Freyermuth, F., Sung, J.C., O'Donovan, K., Fare, C.M., Diaz, Z., Singh, N., Zhang, Z.C., Coughlin, M., Sweeny, E.A., DeSantis, M.E., Jackrel, M.E., Rodell, C.B., Burdick, J.A., King, O.D., Gitler, A.D., Lagier-Tourenne, C., Pandey, U.B., Chook, Y.M., Taylor, J.P., Shorter, J. (2018). Nuclear-Import Receptors Reverse Aberrant Phase Transitions of RNA-Binding Proteins with Prion-like Domains.  Cell 173(3): 677--692.e20.

FBrf0241379

Research paper

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.

PMC5911940 (PMC) (EuropePMC)