Nuclear-Import Receptors Reverse Aberrant Phase Transitions of RNA-Binding Proteins with Prion-like Domains.
Nuclear-Import Receptors Reverse Aberrant Phase Transitions of RNA-Binding Proteins with Prion-like Domains.
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DOI：
10.1016/j.cell.2018.03.002
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发表时间：
2018-04-19
期刊：
影响因子：
64.5
通讯作者：
Shorter J
中科院分区：
文献类型：
--
作者：
Guo L;Kim HJ;Wang H;Monaghan J;Freyermuth F;Sung JC;O'Donovan K;Fare CM;Diaz Z;Singh N;Zhang ZC;Coughlin M;Sweeny EA;DeSantis ME;Jackrel ME;Rodell CB;Burdick JA;King OD;Gitler AD;Lagier-Tourenne C;Pandey UB;Chook YM;Taylor JP;Shorter J
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.
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影响因子：
25
作者：
Chou CC;Zhang Y;Umoh ME;Vaughan SW;Lorenzini I;Liu F;Sayegh M;Donlin-Asp PG;Chen YH;Duong DM;Seyfried NT;Powers MA;Kukar T;Hales CM;Gearing M;Cairns NJ;Boylan KB;Dickson DW;Rademakers R;Zhang YJ;Petrucelli L;Sattler R;Zarnescu DC;Glass JD;Rossoll W
通讯作者：
Rossoll W
DOI：
10.1042/bcj20160499
发表时间：
2017-04-07
期刊：
The Biochemical journal
影响因子：
--
作者：
Harrison AF;Shorter J
通讯作者：
Shorter J
影响因子：
16.2
作者：
Kim HJ;Taylor JP
通讯作者：
Taylor JP
影响因子：
9.8
作者：
Ju S;Tardiff DF;Han H;Divya K;Zhong Q;Maquat LE;Bosco DA;Hayward LJ;Brown RH Jr;Lindquist S;Ringe D;Petsko GA
通讯作者：
Petsko GA
影响因子：
4.8
作者：
Johnson, Brian S.;Snead, David;Gitler, Aaron D.
通讯作者：
Gitler, Aaron D.