| Project/Area Number |
17H04070
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Experimental pathology
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| Research Institution | National Center for Global Health and Medicine |
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Principal Investigator |
Toyama-Sorimachi Noriko 国立研究開発法人国立国際医療研究センター, その他部局等, 分子炎症制御プロジェクト長 (30217468)
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| Project Period (FY) |
2017-04-01 – 2020-03-31
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| Project Status |
Completed (Fiscal Year 2019)
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| Budget Amount *help |
¥17,810,000 (Direct Cost: ¥13,700,000、Indirect Cost: ¥4,110,000)
Fiscal Year 2019: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000)
Fiscal Year 2018: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000)
Fiscal Year 2017: ¥7,020,000 (Direct Cost: ¥5,400,000、Indirect Cost: ¥1,620,000)
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| Keywords | アミノ酸トランスポーター / マスト細胞 / リソソーム / mTORC1 / 炎症 / ｍTOR / エンドリソソーム / アレルギー / 免疫学 |
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| Outline of Final Research Achievements |
Solute carrier family (SLC) member 15A4 is a lysosome-resident, proton-coupled oligopeptide transporter, and preferentially expressed in immune cells, including dendritic cells and B cells. SLC15A4 is critical for the TLR7- and TLR9-mediated inflammatory responses, for which SLC15A4’s transporter activity is required to optimize pH and other conditions in the late endosomes/ lysosomes for lysosome-dependent signaling events including mTORC1 activation.
In the current study, we revealed that the biogenesis and maintenance of secretory granules of mast cells is strictly dependent on SLC15A4. Our results indicated that SLC15A4 promotes the proper function of the mTORC1-TFEB axis in mast cells, and that TFEB dysregulation alters secretory-granule conditions, disturbing mast-cell secretory functions and the IL-33 signaling pathway. Furthermore, we revealed a novel regulation mechanism of mast cell homeostasis, in which type I interferon controls lysosome-related organelle biogenesis.
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| Academic Significance and Societal Importance of the Research Achievements |
マスト細胞はアレルギー応答を担う細胞であり、分泌顆粒の放出によって即時型アレルギー応答が惹起されるほか、免疫応答の調節に重要な役割を果たす。アミノ酸トランスポーターSLC15A4およびI型インターフェロンによるマスト細胞の分泌顆粒形成の制御機構は、新規メカニズムの発見であり、アレルギー応答におけるマスト細胞の機能制御法の開発に有益な知見である。またリソソームと分泌顆粒の生合成制御は不明な点が多く、本研究は、免疫学や細胞生物学領域に新規性の高い知見を導入したのみならず、I型インターフェロンが用いられる肥満細胞腫治療に新たな可能性を提示するものである。
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