A novel regulatory mechanism of autoimmune disease pathogenesis by SLC15A4
| Project/Area Number |
26293090
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Partial Multi-year Fund |
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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 |
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| Co-Investigator(Renkei-kenkyūsha) |
KOBAYASHI TOSHIHIKO 国立国際医療研究センター研究所, 分子炎症制御プロジェクト, 副プロジェクト長 (40613203)
OKAMURA TADASHI 国立国際医療研究センター研究所, ヒト型動物開発研究室, 室長 (00333790)
SHIMIZU YUKIKO 国立国際医療研究センター研究所, ヒト型動物開発研究室, 研究員 (00469983)
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| Project Period (FY) |
2014-04-01 – 2017-03-31
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| Project Status |
Completed (Fiscal Year 2016)
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| Budget Amount *help |
¥16,120,000 (Direct Cost: ¥12,400,000、Indirect Cost: ¥3,720,000)
Fiscal Year 2016: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2015: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000)
Fiscal Year 2014: ¥6,110,000 (Direct Cost: ¥4,700,000、Indirect Cost: ¥1,410,000)
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| Keywords | 炎症 / 自己免疫疾患 / アレルギー / トランスポーター / mTOR / Toll様受容体 / マスト細胞 / 免疫学 / シグナル伝達 / アミノ酸トランスポーター / リソソーム / 全身性エリテマトーデス / 抗体 / I型インターフェロン |
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| Outline of Final Research Achievements |
A lysosome-resident, amino acid/oligopeptide transporter, SLC15A4, plays a crucial role in the pathogenesis of inflammatory diseases through regulation of TLR7/9-mediated type I interferon (IFN-I) productions. We found in this study that SLC15A4 loss caused the accumulations of histidine and histamine in the lysosomes, which resulted in the dysregulation of lysosomal pH. Moreover, SLC15A4-deficient cells showed the decrease of vATPase and mTORC1 activities. Our results indicated that SLC15A4 is an integral part of TLR7/9-triggered inflammatory signals by engaging the lysosomal conditioning. We also found that SLC15A4 regulated mast cell’s functions through the regulation of mTORC1 activity, and played an important role in secretory granule biogenesis and allergic inflammation. These results revealed that SLC15A4-dependent regulation of mTORC1 signaling pathway has an impact not only on various immune cell functions but also on the pathogenic conditions of inflammatory diseases.
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Report
(4 results)
Research Products
(32 results)
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[Journal Article] The histidine transporter SLC15A4 coordinates mTOR-dependent inflammatory responses and pathogenic antibody production.2014
Author(s)
Kobayashi T, Demoto-Shimabukuro S, Yoshida-Sugitani R, Furuyama-Tanaka K, Karyu H, Sugiura Y, Shimizu Y, Hosaka T, Goto M, Kato N, Okamura T, Suematsu M, Yokoyama S, Toyama-Sorimachi N
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Journal Title
Immunity
Volume: 41
Issue: 3
Pages: 375-88
DOI
Related Report
Peer Reviewed / Acknowledgement Compliant
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[Presentation] Ca2+/カルモジュリン依存性プロテインキナーゼ阻害ペプチドを用いた破骨細胞分化制御2016
Author(s)
7.西川喜代孝, 田口祐, 大西 弘晃, 藤原誠, 西園貴志, 西村浩輝, 小林俊彦, 反町典子, 高柳広, 尾藤晴彦, 井上純一郎, 高橋美帆
Organizer
第２回日本骨免疫学会
Place of Presentation
沖縄
Year and Date
2016-07-06
Related Report
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