Regulatory mechanism of mTOC1 signaling by ubiquitin ligase RNF182 involved in neural differentiation
| Project/Area Number |
18K06685
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Review Section |
Basic Section 47040:Pharmacology-related
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| Research Institution | Nagasaki University (2020-2021)
Hiroshima University (2018-2019) |
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Principal Investigator |
Kaneko Masayuki 長崎大学, 医歯薬学総合研究科(薬学系), 教授 (10322827)
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| Co-Investigator(Kenkyū-buntansha) |
高田 修治 国立研究開発法人国立成育医療研究センター, システム発生・再生医学研究部, 部長 (20382856)
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| Project Period (FY) |
2018-04-01 – 2022-03-31
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| Project Status |
Completed (Fiscal Year 2021)
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| Budget Amount *help |
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
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| Keywords | ユビキチンリガーゼ / mTORC1 / RNF182 / 神経分化 / リソソーム / LAPTM4A / LAT1 / ユビキチン / LAPTM / アミノ酸トランスポーター / RNF183 / トランスポーター / ビオチンリガーゼ / ノックイン / ライソゾーム / TFEB / mTOR / ユビキチン化 |
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| Outline of Final Research Achievements |
In the present study, we investigated the role of RNF182, which is a central nervous system-specific ubiquitin ligase localized in lysosomes, in neural differentiation. We found that RNF182 poly-ubiquitylates lysosomal-associated transmembrane protein LAPTM4A via K63-linked chains. LAPTM family reportedly participates in the recruitment of the large neutral amino acid transporter LAT1 to lysosomes, leading to leucine uptake into lysosomes and mammalian target of rapamycin complex 1 (mTORC1) activation. We showed that the RNF182-mediated poly-ubiquitylation of LAPTMs facilitated the interaction of LAPTMs with LAT1 and the stabilization of LAT1 in lysosome membranes. In addition, we found that RNF182 expression was induced by the lysosome inhibitor chloroquine and the transcription factor TFEB, which is activated by lysosomal stress.
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| Academic Significance and Societal Importance of the Research Achievements |
リソソーム膜に局在するアミノ酸トランスポーターは、栄養素・エネルギー状態のセンサーmTORC1の活性化に関与することが報告されており、RNF182はLAPTM4Aのユビキチン化を介したアミノ酸トランスポーターのリソソームへの局在化によりmTORC1シグナルの調節に働くと考えられる。リソソームストレスによる遺伝子誘導ではmTORC1がセンサーとなっており、RNF182はそのフィードバックに関わっている可能性が示唆される。mTORC1はがんやオートファジーとの関連性が知られているが、今後は神経分化への関与について生体レベルでも明らかにしていきたい。
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Report
(5 results)
Research Products
(52 results)
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[Journal Article] NFAT5 up-regulates expression of the kidney-specific ubiquitin ligase gene Rnf183 under hypertonic conditions in inner-medullary collecting duct cells.2019
Author(s)
Maeoka Y, Wu Y, Okamoto T, Kanemoto S, Guo XP, Saito A, Asada R, Matsuhisa K, Masaki T, Imaizumi K, Kaneko M.
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Journal Title
Journal of Biological Chemistry
Volume: 294
Pages: 101-115
DOI
Related Report
Peer Reviewed / Int'l Joint Research
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[Journal Article] Shutdown of ER-associated degradation pathway rescues functions of mutant iduronate 2-sulfatase linked to mucopolysaccharidosis type II.2018
Author(s)
Osaki Y, Saito A, Kanemoto S, Kaneko M, Matsuhisa K, Asada R, Masaki T, Orii K, Fukao T, Tomatsu S, Imaizumi K
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Journal Title
Cell Death & Disease
Volume: 9
Pages: 808-808
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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