김홍주 (St. Jude Children’s Research Hospital)

한빛사논문

조회2,316

St. Jude Children’s Research Hospital

CV File 71 kb

Cell, Published: April 19, 2018 | DOI: https://doi.org/10.1016/j.cell.2018.03.002 Nuclear-Import Receptors Reverse Aberrant Phase Transitions of RNA-Binding Proteins with Prion-like Domains

Lin Guo,^1,13 Hong Joo Kim,^2,13 Hejia Wang,^1,13 John Monaghan,^3,12,14 Fernande Freyermuth,^4,5,14 Julie C. Sung,^1,14 Kevin O’Donovan,² Charlotte M. Fare,¹ Zamia Diaz,¹ Nikita Singh,¹ Zi Chao Zhang,^6,7 Maura Coughlin,² Elizabeth A. Sweeny,¹ Morgan E. DeSantis,¹ Meredith E. Jackrel,¹ Christopher B. Rodell,⁸ Jason A. Burdick,⁸ Oliver D. King,⁹Aaron D. Gitler,¹⁰ Clotilde Lagier-Tourenne,^4,5 Udai Bhan Pandey,³ Yuh Min Chook,⁶ J. Paul Taylor,^2,11,* and James Shorter^1,15,*¹Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA

²Department of Cell and Molecular Biology, St. Jude Children’s Research Hospital, Memphis, TN 38120, USA

³Department of Pediatrics, Child Neurology and Neurobiology, Children’s Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, PA 15224, USA

⁴Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA

⁵Broad Institute of Harvard University and MIT, Cambridge, MA 02142, USA

⁶Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA

⁷Institute of Life Sciences, Southeast University, Nanjing, 210096 Jiangsu, China

⁸Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104, USA

⁹Department of Neurology, University of Massachusetts Medical School, Worcester, MA 01655, USA

¹⁰Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA

¹¹Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA

¹²Present address: School of Medicine, Trinity College Dublin, Dublin, Ireland

¹³These authors contributed equally

¹⁴These authors contributed equally

¹⁵Lead Contact

^*Correspondence: J. Paul Taylor, James Shorter

Abstract

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.

논문정보

형식Research article
게재일2018년 04월 (BRIC 등록일 2018-04-26)
연구진국외 연구진
분야 생명과학 > 세포생물학

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