A role of Arl8b for the development of SLE

• Project/Area Number: 26293083
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Experimental pathology
• Research Institution: The University of Tokyo
• Principal Investigator: Saitoh Shin-Ichiroh 東京大学, 医科学研究所, 准教授 (90361625)
• Project Period (FY): 2014-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥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: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000); Fiscal Year 2014: ¥5,980,000 (Direct Cost: ¥4,600,000、Indirect Cost: ¥1,380,000)
• Keywords: 全身性エリテマトーデス / Arl8b / 自己免疫疾患 / 形質細胞様樹状細胞 / Toll-like Receptor 7 / 低分子量G蛋白質 / SLEモデルマウス / 1型インターフェロン / 制御性T細胞 / 全身性エリトマトーデス / Toll-like receptor 7 / 低分子量Gタンパク質 / MRL-lpr / TLR7 / small G protein / 樹状細胞

Outline of Final Research Achievements

lysosomal small G protein Arl8b is associated with Toll-like Receptor 7(TLR7), which is an RNA sensor recognizing viral or bacterial RNA in endosome or lysosome. We clarified that Arl8b is essential for the development of Systemic lupus erythematosus (SLE) in TLR7 and type 1 Interferon dependent SLE mouse models, BXSB.Yaa and TMPD-induced SLE. We reported that Arl8b plays an important role for TLR7 dependent type 1 Interferon expression in pDC. We also analyzed another type of SLE model, MRL/lpr. It is not TLR7 and type 1 dependent SLE model so much. We found that Arl8b is also essential for the development of SLE in TLR7 and type 1 Interferon independent mechanism in MRL/lpr. Arl8b controls regulatory T cells and the development of SLE in this model.

Research Products

• [Journal Article] Mechanisms controlling nucleic acid-sensing Toll-like receptors (2018)
  • Author(s): Miyake Kensuke、Shibata Takuma、Ohto Umeharu、Shimizu Toshiyuki、Saitoh Shin-Ichiroh、Fukui Ryutaro、Murakami Yusuke
  • Journal Title: International Immunology Volume: 30 Issue: 2 Pages: 43-51
  • DOI: 10.1093/intimm/dxy016
  • Peer Reviewed / Open Access
• [Journal Article] Epithelial membrane protein 3 (Emp3) downregulates induction and function of cytotoxic T lymphocytes by macrophages via TNF-α production (2018)
  • Author(s): Kusumoto Yutaka、Okuyama Hiromi、Shibata Takuma、Konno Kazunori、Takemoto Yusuke、Maekawa Daisuke、Kononaga Tomoyuki、Ishii Takashi、Akashi-Takamura Sachiko、Saitoh Shin-ichiroh、Ikebuchi Ryoyo、Moriya Taiki、Ueda Mizuki、Miyake Kensuke、Ono Shiro、Tomura Michio
  • Journal Title: Cellular Immunology Volume: 324 Pages: 33-41
  • DOI: 10.1016/j.cellimm.2017.12.001
  • Peer Reviewed / Open Access
• [Journal Article] TLR7 mediated viral recognition results in focal type I interferon secretion by dendritic cells (2017)
  • Author(s): Saitoh SI, Abe F, Kanno A, Tanimura N, Mori Saitoh Y, Fukui R, Shibata T, Sato K, Ichinohe T, Hayashi M, Kubota K, Kozuka-Hata H, Oyama M, Kikko Y, Katada T, Kontani K and Miyake K
  • Journal Title: Nat Commun Volume: 8 Issue: 1 Pages: 1592-1592
  • DOI: 10.1038/s41467-017-01687-x
  • Peer Reviewed / Open Access
• [Journal Article] The protective effect of the anti-Toll-like receptor 9 antibody against acute cytokine storm caused by immunostimulatory DNA (2017)
  • Author(s): Murakami Y, Fukui R, Motoi Y, Shibata T, Saitoh SI, Sato R, Miyake K.
  • Journal Title: Scientific Report Volume: 7 Issue: 1 Pages: 44042-44054
  • DOI: 10.1038/srep44042
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Core fucose is critical for CD14-dependent Toll-like receptor 4 signaling (2017)
  • Author(s): 4.Iijima J, Kobayashi S, Kitazume S*, Kizuka Y, Fujinawa R, Korekane H, Shibata T, Saitoh S, Akashi-Takamura S, Miyake K, Miyoshi E, and Taniguch N
  • Journal Title: Glycobiology Volume: 2017 Issue: 11 Pages: 1006-1015
  • DOI: 10.1093/glycob/cwx075
  • Peer Reviewed / Open Access
• [Journal Article] Arl8b is required for lysosomal degradation of maternal proteins in the visceral yolk sac endoderm of mouse embryos (2017)
  • Author(s): Oka M, Hashimoto K, Yamaguchi Y, Saitoh SI, Sugiura Y, Motoi Y, Honda K, Kikko Y, Ohata S, Suematsu M, Miura M, Miyake K, Katada T and Kontani K
  • Journal Title: J Cell Sci Volume: 130 Issue: 20 Pages: 3568-3577
  • DOI: 10.1242/jcs.200519
  • Peer Reviewed / Open Access
• [Journal Article] Endoplasmic Protein Nogo-B (RTN4-B) Interacts with GRAMD4 and Regulates TLR9-Mediated Innate Immune Responses. (2015)
  • Author(s): Kimura T, Endo S, Inui M, Saitoh S, Miyake K, Takai T.
  • Journal Title: J Immunol. Volume: 194 Issue: 11 Pages: 5426-5436
  • DOI: 10.4049/jimmunol.1402006
  • Peer Reviewed / Open Access
• [Journal Article] Roles of the Cleaved N-Terminal TLR3 Fragment and Cell Surface TLR3 in Double-Strand RNA Sensing (2015)
  • Author(s): Murakami Y, Fukui R, Motoi Y, Kanno A, Shibata T, Tanimura N, Saitoh S, Miyake K
  • Journal Title: Journal of Immunology Volume: 193 Issue: 10 Pages: 5208-5217
  • DOI: 10.4049/jimmunol.1400386
  • Peer Reviewed
• [Journal Article] Mucolipin 1 positively regulates TLR7 responses in dendritic cells by facilitating RNA transportation to lysosomes (2015)
  • Author(s): Li X, Saitoh S, Shibata T, Tanimura N, Fukui R, Miyake K.
  • Journal Title: International immunology Volume: 27 Issue: 2 Pages: 83-94
  • DOI: 10.1093/intimm/dxu086
  • Peer Reviewed / Open Access
• [Journal Article] DNase II-dependent DNA digestion is required for DNA sensing by TLR9 (2015)
  • Author(s): Chan MP, Onji M, Fukui R, Kawane K, Shibata T, Saitoh SI, Ohto U, Shimizu T, Barber GN, *Miyake K
  • Journal Title: Nat Commun Volume: 6 Issue: 1 Pages: 5853-5853
  • DOI: 10.1038/ncomms6853
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Targeting cell surface TLR7 for therapeutic intervention in autoimmune diseases (2015)
  • Author(s): Kanno A, Tanimura N, Ishizaki M, Ohko K, Motoi Y, Onji M, Fukui R, Shimozato T, Yamamoto K, Shibata T, Sano S, Sugahara-Tobinai A, Takai T, Ohto U, Shimizu T, Saitoh S, Miyake K.
  • Journal Title: Nature Communications Volume: 6 Issue: 1 Pages: 6119-6119
  • DOI: 10.1038/ncomms7119
  • Peer Reviewed / Open Access
• [Journal Article] The attenuated inflammation of MPL is due to the lack of CD14-dependent tight dimerization of TLR4/MD2 complex at the plasma membrane (2013)
  • Author(s): Tanimura N, Saitoh S, Ohto U, Akashi-Takamura A, Fujimoto Y, Fukase K, Shimizu T, Miyake K
  • Journal Title: Int. Immunol. Volume: 26 Issue: 6 Pages: 307-314
  • DOI: 10.1093/intimm/dxt071
  • Peer Reviewed
• [Presentation] Arl8bは全身性エリテマトーデスモデルマウスBXSB.Yaaの病気の発症に関わっている. (2017)
  • Author(s): 齋藤 伸一郎
  • Organizer: 第23回日本エンドトキシン・自然免疫研究会
• [Presentation] ADP-ribosylation factor-like 8b is required for the pathogenesis of mouse models of Systemic Lupus Erythematosus. (2017)
  • Author(s): Shin-Ichiroh Saitoh, Yoshiko Mori Saitoh, Katsuaki Sato, Kenji Kontani, and Kensuke Miyake
  • Organizer: 第46回日本免疫学会学術集会
• [Presentation] Metabolic permission for IFNa induction is connected by Toll-like Receptor 7 trafficking (2016)
  • Author(s): Shin-Ichiroh Saitoh
  • Organizer: 日本免疫学会
  • Place of Presentation: 沖縄コンベンションセンター
  • Year and Date: 2016-12-05
  • Invited
• [Presentation] Toll-like receptor 7の移動は代謝センサーmTorC1による1型インターフェロン産生の制御と結びついている (2016)
  • Author(s): 齋藤 伸一郎
  • Organizer: 日本エンドトキシン・自然免疫研究会
  • Place of Presentation: 鹿児島大学 郡元キャンパス
  • Year and Date: 2016-12-02
• [Book] Toll-like Receptor 7が1型インターフェロンを産生するにはLFA-1が重要な役割を果たしている (2017)
  • Author(s): 齋藤 伸一郎
  • Total Pages: 3
  • Publisher: 日本エンドトキシン・自然免疫研究会
• [Remarks] 東京大学医科学研究所 感染遺伝学
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• [Remarks] 東京大学医科学研究所Annual report
  • URL: http://www.ims.u-tokyo.ac.jp/imsut/jp/about/publication/annualreport/
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• [Remarks] 東京大学医科学研究所感染遺伝学分野
  • URL: http://www.ims.u-tokyo.ac.jp/kanseniden/
• [Remarks] 東京大学医科学研究所Annual Report
  • URL: http://www.ims.u-tokyo.ac.jp/imsut/jp/about/publication/annualreport/