Casein kinase 1δ/ε phosphorylates fused in sarcoma (FUS) and ameliorates FUS-mediated neurodegeneration
Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved..
Aberrant cytoplasmic accumulation of an RNA-binding protein, fused in sarcoma (FUS), characterizes the neuropathology of subtypes of ALS and frontotemporal lobar degeneration, although the effects of post-translational modifications of FUS, especially phosphorylation, on its neurotoxicity have not been fully characterized. Here, we show that casein kinase 1δ (CK1δ) phosphorylates FUS at 10 serine/threonine residues in vitro using mass spectrometric analyses. We also show that phosphorylation by CK1δ or CK1ε significantly increased the solubility of FUS in human embryonic kidney 293 cells. In transgenic Drosophila that overexpress wt or P525L ALS-mutant human FUS in the retina or in neurons, we found coexpression of human CK1δ or its Drosophila isologue Dco in the photoreceptor neurons significantly ameliorated the observed retinal degeneration, and neuronal coexpression of human CK1δ extended fly life span. Taken together, our data suggest a novel regulatory mechanism of the assembly and toxicity of FUS through CK1δ/CK1ε-mediated phosphorylation, which could represent a potential therapeutic target in FUS proteinopathies.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2022 |
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| Erschienen: |
2022 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:298 |
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| Enthalten in: |
The Journal of biological chemistry - 298(2022), 8 vom: 25. Aug., Seite 102191 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Kishino, Yuya [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 08.09.2022 Date Revised 18.10.2022 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.jbc.2022.102191 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM342743465 |
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| 100 | 1 | |a Kishino, Yuya |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Casein kinase 1δ/ε phosphorylates fused in sarcoma (FUS) and ameliorates FUS-mediated neurodegeneration |
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| 500 | |a published: Print-Electronic | ||
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| 520 | |a Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved. | ||
| 520 | |a Aberrant cytoplasmic accumulation of an RNA-binding protein, fused in sarcoma (FUS), characterizes the neuropathology of subtypes of ALS and frontotemporal lobar degeneration, although the effects of post-translational modifications of FUS, especially phosphorylation, on its neurotoxicity have not been fully characterized. Here, we show that casein kinase 1δ (CK1δ) phosphorylates FUS at 10 serine/threonine residues in vitro using mass spectrometric analyses. We also show that phosphorylation by CK1δ or CK1ε significantly increased the solubility of FUS in human embryonic kidney 293 cells. In transgenic Drosophila that overexpress wt or P525L ALS-mutant human FUS in the retina or in neurons, we found coexpression of human CK1δ or its Drosophila isologue Dco in the photoreceptor neurons significantly ameliorated the observed retinal degeneration, and neuronal coexpression of human CK1δ extended fly life span. Taken together, our data suggest a novel regulatory mechanism of the assembly and toxicity of FUS through CK1δ/CK1ε-mediated phosphorylation, which could represent a potential therapeutic target in FUS proteinopathies | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a ALS | |
| 650 | 4 | |a CK1δ/ε | |
| 650 | 4 | |a Drosophila | |
| 650 | 4 | |a frontotemporal lobar degeneration | |
| 650 | 4 | |a fused in sarcoma | |
| 650 | 4 | |a neurodegeneration | |
| 650 | 4 | |a phosphorylation | |
| 650 | 7 | |a Drosophila Proteins |2 NLM | |
| 650 | 7 | |a FUS protein, human |2 NLM | |
| 650 | 7 | |a RNA-Binding Protein FUS |2 NLM | |
| 650 | 7 | |a dco protein, Drosophila |2 NLM | |
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| 700 | 1 | |a Matsukawa, Koji |e verfasserin |4 aut | |
| 700 | 1 | |a Matsumoto, Taisei |e verfasserin |4 aut | |
| 700 | 1 | |a Miyazaki, Ryota |e verfasserin |4 aut | |
| 700 | 1 | |a Wakabayashi, Tomoko |e verfasserin |4 aut | |
| 700 | 1 | |a Nonaka, Takashi |e verfasserin |4 aut | |
| 700 | 1 | |a Kametani, Fuyuki |e verfasserin |4 aut | |
| 700 | 1 | |a Hasegawa, Masato |e verfasserin |4 aut | |
| 700 | 1 | |a Hashimoto, Tadafumi |e verfasserin |4 aut | |
| 700 | 1 | |a Iwatsubo, Takeshi |e verfasserin |4 aut | |
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