Spatiotemporal regulation of nucleic acid uptake and signaling

2013 Fiscal Year Final Research Report

• Project/Area Number: 23590558
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Immunology
• Research Institution: Hokkaido University
• Principal Investigator: MATSUMOTO Misako 北海道大学, 医学(系)研究科(研究院), 特任准教授 (30332456)
• Co-Investigator(Renkei-kenkyūsha): SEYA Tsukasa 北海道大学, 大学院医学研究科, 教授 (10301805)
• Project Period (FY): 2011 – 2013
• Keywords: 自然免疫 / Toll-like receptor / エンドソーム / 樹状細胞 / RNA認識 / ウイルス感染 / 炎症応答 / マクロファージ

Research Abstract

Endosomal Toll-like receptor (TLR) 3 serves as a sensor of viral infection and sterile tissue necrosis and activates innate and adaptive immunity. Although TLR3 recognizes double-stranded (ds) RNA, little is known about structural features of virus- or host-derived RNAs that activate TLR3 in infection/inflammatory states. In this study, we demonstrate that single-stranded RNAs harboring stable incomplete stem structures are potent TLR3 agonists. Like poly(I:C), a synthetic dsRNA, these structured RNAs were internalized into cells via raftlin-mediated endocytosis and activated TLR3. Based on the ligand recognition mode of TLR3 and uptake mechanism of extracellular nucleic acids, we have generated novel TLR3 ligand that activates endosomal TLR3 but not cytoplasmic RNA sensors.

Research Products

• [Journal Article] IPS-1 is essential for type III interferon production by hepatocytes and dendritic cells in response to hepatitis C virus infection (2014)
  • Author(s): Okamoto, M., H. Oshiumi, M. Azuma, M. Matsumoto, and T. Seya.
  • Journal Title: J . Immunol Volume: 192(6) Pages: 2770-2777
• [Journal Article] Myeloid-derived suppressor cells confer tumor-suppressive functions on natural killer cells via polyinosinic : polycytidylic acid treatment in mouse tumor model (2014)
  • Author(s): Shime, H., A. Kojima, A. Maruyama, Y. Saito, H. Oshiumi, M. Matsumoto, and T. Seya.
  • Journal Title: J . Innate. Immun Volume: 6 Pages: 293-305
• [Journal Article] The N-terminal domain of TIR domain-containing adaptor molecule-1, TICAM-1 (2014)
  • Author(s): Kumeta, H., H. Sakakibara, Y. Enokizono, K. Ogura, M. Horiuchi, M. Matsumoto, T. Seya, and F. Inagaki.
  • Journal Title: J. Biomolec. NMR Volume: 58(3) Pages: 227-230
• [Journal Article] Beyond double-stranded RNA : TLR3 signaling in RNA-induced immune responses (2014)
  • Author(s): Tatematsu M, T. Seya, and M. Matsumoto.
  • Journal Title: Biochem. J . Volume: 458 (2) Pages: 195-201
• [Journal Article] Cell type-specific subcellular localization of phospho-TBK1 in response to cytoplasmic viral DNA (2013)
  • Author(s): Suzuki, T., H. Oshiumi, M. Miyashita, H. H. Aly, M. Matsumoto, and T. Seya.
  • Journal Title: PLos ONE Volume: 8(12) Pages: e83639
• [Journal Article] Structures and interface mapping of the TIR-domain-containing adaptor molecules involved in interferon signaling (2013)
  • Author(s): Enokizono, Y., H. Kumeta, K. Funami, M. Horiuchi, J. Sarmiento, K. Yamashita, D. Standley, M. Matsumoto, T. Seya, and F. Inagaki.
  • Journal Title: Proc. Natl. Acad. Sci. U. S. A. Volume: 110(49) Pages: 19908-19913
• [Journal Article] The MyD88 pathway in plasmacytoid and CD4^+ dendritic cells primarily triggers type I interferon production against measles virus in a mouse infection model (2013)
  • Author(s): Takaki, H., M. Takeda, M. Tahara, M. Shingai, Oshiumi, M. Matsumoto, and T. Seya.
  • Journal Title: J . Immunol Volume: 191(9) Pages: 4740-4747
• [Journal Article] MAVS-dependent IRF3/7 bypass of interferon b-induction restricts the response to measles infection in CD150Tg mouse bone marrow-derived dendritic cells (2013)
  • Author(s): Takaki, H., K. Honada, K. Atarashi, F. Kobayashi, T. Ebihara, H. Oshiumi, M. Matsumoto, M. Shingai, and T. Seya.
  • Journal Title: Mol Immunol Volume: 57(2) Pages: 100-110
• [Journal Article] A Distinct role of Riplet-mediated K63-linked polyubiquitination of the RIG-I repressor domain in human antiviral innate immune responses (2013)
  • Author(s): Oshiumi, H., M. Miyashita, M. Matsumoto, and T. Seya.
  • Journal Title: PLoS Pathog Volume: 9(8) Pages: e1003533
• [Journal Article] Toll-like receptor 3 recognizes incomplete stem structures in single-stranded viral RNA (2013)
  • Author(s): Tatematsu, M., F. Nishikawa, T. Seya, and M. Matsumoto.
  • Journal Title: Nat. Commun Volume: 4 Pages: 1833
• [Journal Article] Cleaved/associated TLR3 represents the primary form of the signaling receptor (2013)
  • Author(s): Toscano F., Y. Estornes, F. Virard, A. Garcia-Cattaneo, A. Pierrot, B. Vanbervliet, M. Bonnin, M. J. Ciancanelli, S-Y. Zhang, K. Funami, T. Seya, M. Matsumoto, J-J. Pin, J-L. Casanova, T. Renno, and S. Lebecque.
  • Journal Title: J Immunol Volume: 190(2) Pages: 764-773
• [Journal Article] Targeting TLR3 with no RIG-I/MDA5 activation is effective in immunotherapy for cancer (2013)
  • Author(s): Seya T., M. Azuma, and M. Matsumoto.
  • Journal Title: Expert Opin. Ther. Targets Volume: 17(5) Pages: 533-544
• [Journal Article] Multi-step regulation of interferon induction by hepatitis C virus (2013)
  • Author(s): Oshiumi H., K. Funami, H. H. Aly, M. Matsumoto, and T. Seya.
  • Journal Title: Arch Immunol Ther Exp (Warsz) Volume: 61(2) Pages: 127-138
• [Journal Article] 抗がん免疫アジュバント:歴史から現状まで (2013)
  • Author(s): 瀬谷司、松本美佐子
  • Journal Title: 実験医学 Volume: 31(12) Pages: 107-113
• [Journal Article] TLR3免疫アジュバントの開発 (2013)
  • Author(s): 松本美佐子、瀬谷司
  • Journal Title: 医学のあゆみ Volume: 244(9) Pages: 794-799
• [Journal Article] Cross-priming for anti-tumor CTL induced by soluble Ag + polyI : C depends on the TICAM-1 pathway in mouse CD11c+/CD8a+ dendritic cells (2012)
  • Author(s): Azuma, M., T. Ebihara, H. Oshiumi, M. Matsumoto, and T. Seya.
  • Journal Title: Oncoimmunology Volume: 1(5) Pages: 581-592
• [Journal Article] Dendritic cells from oral cavity induce Foxp3^+ regulatory T cells upon antigen stimulation (2012)
  • Author(s): Yamazaki S., A, Maruyama, K. Okada, M. Matsumoto, A. Morita, and T. Seya.
  • Journal Title: PLoS ONE Volume: 7(12) Pages: e51665
• [Journal Article] Toll-like receptor 3 signaling converts tumor-supporting myeloid cells to tumoricidal effectors (2012)
  • Author(s): Shime, H., M. Matsumoto, H. Oshiumi, S. Tanaka, A. Nakane, Y. Iwakura, H. Tahara, N. Inoue, T. Seya.
  • Journal Title: Proc. Natl. Acad. Sci. U. S. A. Volume: 109(6) Pages: 2066-2071
• [Journal Article] Complement C1q activates canonical Wnt signaling and promotes aging-related phenotypes (2012)
  • Author(s): Naito, A. T., T. Sumida, S. Nomura, M-L Liu, T. Higo, K. A. Nakagawa, Okada, T. Sakai, A. A. Hashimoto, Y. Hara, I. Shimizu, W. Zhu, H. Toko, A. Katada, H. Akazawa, T. Oka, J-K. Lee, T. Minamino, T. Nagai, K. Walsh, A. Kikuchi, M. Matsumoto, M. Botto, I. Shiojima, and I. Komuro.
  • Journal Title: Cell Volume: 149(6) Pages: 1298-1313
• [Journal Article] The Toll-like receptor 3-mediayed antiviral response is important for protection against poliovirus infection in poliovirus receptor transgenic mice (2012)
  • Author(s): Abe, Y., K. Fujii, N. Nagata, O. Takeuchi, S. Akira, H. Oshiumi, M. Matsumoto, T. Seya, and S. Koike.
  • Journal Title: J . Virol Volume: 86(1) Pages: 185-194
• [Journal Article] TLR3/TICAM-1 signaling in tumor cell RIP3-dependent necroptosis (2012)
  • Author(s): Seya, T., H. Shime, H. Takaki, M. Azuma, H. Oshiumi, and M. Matsumoto.
  • Journal Title: Oncoimmunology Volume: 1(6) Pages: 917-923
• [Journal Article] 自然免疫と癌治療 (2012)
  • Author(s): 瀬谷司、松本美佐子
  • Journal Title: 医学のあゆみ Volume: 243 (1) Pages: 115-121
• [Journal Article] ネクローシス細胞による炎症惹起の機序 (2012)
  • Author(s): 瀬谷司、志馬寛明、松本美佐子
  • Journal Title: 臨床免疫・アレルギー科 Volume: 57(6) Pages: 674-680
• [Journal Article] ウイルス感染による自然免疫活性化機構 (2012)
  • Author(s): 松本美佐子、押海裕之、瀬谷司
  • Journal Title: 炎症と免疫先端医学社 Volume: 20(1) Pages: 3-8
• [Journal Article] UNC93B1 physically associates with human TLR8 and regulates TLR8-mediated signaling (2011)
  • Author(s): Itoh, H., M. Tatematsu, A. Watanabe, K. Iwano. K. Funami, T. Seya and M. Matsumoto.
  • Journal Title: PLoS ONE Volume: 6(12) Pages: e28500
• [Journal Article] Herpes simplex encephalitis in children with autosomal recessive and dominant TRIF deficiency (2011)
  • Author(s): Sancho-Shimizu V, Pérez de Diego R, Lorenzo L, Seya T, Matsumoto M, et al.
  • Journal Title: J . Clin. Invest Volume: 121(12) Pages: 4889-4902
• [Journal Article] The TLR3-TICAM-1 pathway is mandatory for innate immune responses to poliovirus infection (2011)
  • Author(s): Oshiumi, H., M. Okamoto, K. Fujii, T. Kawanishi, M. Matsumoto, S. Koike, and T. Seya.
  • Journal Title: J . Immunol Volume: 15; 187 Pages: 5320-5327
• [Journal Article] Phosphoinositide 3-kinaseg controls the intracellular localization of CpG to limit DNA-PKcs-dependent IL-10 production in macrophages (2011)
  • Author(s): Hazeki, K., Y. Kametani, H. Murakami, M. Uehara, Y. Ishikawa, K. Nigorokawa, S. Takasuga, T. Sasaki, T. Seya, M. Matsumoto, and O. Hazeki.
  • Journal Title: PLoS ONE Volume: 6 (10) Pages: e26836
  • DOI: 10.1371/journal.pone.0026836
• [Journal Article] DDX60, a DHXD/H box helicase, is a novel antiviral factor promoting RIG-I-like receptor-mediated signaling (2011)
  • Author(s): Miyashita, M., H. Oshiumi, M. Matsumoto, and T. Seya.
  • Journal Title: Mol. Cell Biol Volume: 31(18) Pages: 3802-3819
• [Journal Article] Development of mouse hepatocyte lines permissive for hepatitis C virus (HCV) (2011)
  • Author(s): Aly, H. H., H. Oshiumi, H. Shime, M. Matsumoto, T. Wakita, K. Shimotohno, and T. Seya.
  • Journal Title: Plos ONE Volume: 6 (6) Pages: e21284
• [Journal Article] Development of monoclonal antibodies that specifically interact with necrotic lymphoma cells (2011)
  • Author(s): Wakasa K., H. Shime, M. Kurita-Taniguchi, M. Matsumoto, M. Imamura, and T. Seya.
  • Journal Title: Microbiol. Immunol Volume: 55(5) Pages: 373-377
• [Journal Article] TLR2-dependent induction of IL-10 and Foxp3^+CD25^+CD4^+ regulatory T cells prevents effective anti-tumor immunity induced by Pam2 lipopeptides in vivo (2011)
  • Author(s): Yamazaki S., K. Okada, A. Maruyama, M. Matsumoto, H. Yagita, and T. Seya.
  • Journal Title: PLoS ONE Volume: 6 (4) Pages: e18833
• [Journal Article] Raftlin is involved in the nucleocapture complex to induce poly(I : C)-mediated TLR3 activation (2011)
  • Author(s): Watanabe, A. M. Tatematsu, K. Saeki, S. Shibata, H. Shime, A. Yoshimura, C. Obuse, T. Seya, and M. Matsumoto.
  • Journal Title: J . Biol. Chem Volume: 286 Pages: 10702-10711
• [Journal Article] Failure of mycoplasma lipoprotein MALP-2 to induce NK cell activation through dendritic cell TLR2 (2011)
  • Author(s): Sawahata, R., H. Shime, S. Yamazaki, N. Inoue, T. Akazawa, Y. Fujimoto, K. Fukase, M. Matsumoto, and T. Seya.
  • Journal Title: Microbes Infect Volume: 13(4) Pages: 350-358
• [Journal Article] Natural killer cell activation secondary to innate pattern sensing (2011)
  • Author(s): Seya T. J. Kasamatsu, M. Azuma, H. shime, and M. Matsumoto.
  • Journal Title: J . Innate Immun Volume: 3(3) Pages: 264-273
• [Journal Article] Antiviral responses induced by the TLR3 pathway (2011)
  • Author(s): Matsumoto, M., H. Oshiumi, and T. Seya.
  • Journal Title: Rev. Med. Virol Volume: 21 Pages: 67-77
• [Journal Article] RNAウイルス感染に対する自然免疫応答 (2011)
  • Author(s): 押海裕之、松本美佐子、瀬谷司
  • Journal Title: ウイルス、日本ウイルス学会誌 Volume: 61 Pages: 153-162
• [Journal Article] ワクチン増強剤としての抗がんRNAアジュバントの展望 (2011)
  • Author(s): 瀬谷司、松本美佐子
  • Journal Title: 細胞 Volume: 43 (3) Pages: 20-23
• [Journal Article] 自然免疫と癌治療 (2011)
  • Author(s): 瀬谷司、押海裕之、志馬寛明、松本美佐子
  • Journal Title: 実験医学(増刊) Volume: 29(2) Pages: 111-118
• [Journal Article] 食細胞機能の増強 (2011)
  • Author(s): 松本美佐子
  • Journal Title: 補体への招待 Pages: 79-87
• [Presentation] Development of ideal adjuvant for cancer vaccine : Beyond the scope of current immunotherapy for cancer (2014)
  • Author(s): Tsukasa Seya and Misako Matsumoto
  • Organizer: The 4th International Symposium on Carcinogenic Spiral. Infection, Immunity, and Cancer
  • Place of Presentation: 札幌(京王プラザホテル)
  • Year and Date: 2014-02-10
• [Presentation] ヒトToll-like receptor 8のリガンド認識機構の解析 (2013)
  • Author(s): 石井朝子、舟見健児、立松恵、瀬谷司、松本美佐子
  • Organizer: 第36回日本分子生物学会学術集会
  • Place of Presentation: 兵庫
  • Year and Date: 20131203-06
• [Presentation] Raftlin regulates Toll-like receptor 4-mediated signaling (2013)
  • Author(s): Megumi Tatematsu, Ryuji Yoshida, Kazuko Saeki, Tsukasa Seya, Misako Matsumoto
  • Organizer: 第36回日本分子生物学会学術集会
  • Place of Presentation: 兵庫
  • Year and Date: 20131203-06
• [Presentation] TLR3 recognizes single-stranded RNA with incomplete stem structures (2013)
  • Author(s): Megumi Tatematsu, Fumiko Nishikawa, Tsukasa Seya and Misako Matsumoto
  • Organizer: 15th International Congress of Immunology
  • Place of Presentation: Milan, Italy
  • Year and Date: 20130822-27
• [Presentation] 自然免疫レセプターTLR3によって認識されるRNA構造 (2013)
  • Author(s): 松本美佐子
  • Organizer: 第50回補体シンポジウム
  • Place of Presentation: 旭川
  • Year and Date: 2013-07-05
• [Presentation] Role of Raftlin in Toll-Like Receptor 4-mediated Signaling (2012)
  • Author(s): Ryuji Yoshida, Megumi Tatematsu, Tsukasa Seya, Misako Matsumoto
  • Organizer: 第41日本免疫学会学術集会
  • Place of Presentation: 神戸
  • Year and Date: 20121205-07
• [Presentation] Properties of viral single-stranded RNAs that harbor ability for emdosomal TLR3 targeting (2012)
  • Author(s): Megumi Tatematsu, Tsukasa Seya, and Misako Matsumoto
  • Organizer: 第41日本免疫学会学術集会
  • Place of Presentation: 神戸
  • Year and Date: 20121205-07
• [Presentation] ウイルスゲノム由来の一本鎖RNAによるToll-like receptor 3活性化の解析 (2012)
  • Author(s): 立松恵、瀬谷司、松本美佐子
  • Organizer: 第60回日本ウイルス学会学術集会
  • Place of Presentation: 大阪
  • Year and Date: 20121113-15
• [Presentation] Toll-like receptor 3による核酸認識とシグナル伝達 (2012)
  • Author(s): 松本美佐子
  • Organizer: 第16回日本がん免疫学会総会
  • Place of Presentation: 札幌
  • Year and Date: 20120726-28
• [Presentation] What immune responses are evoked by selective stimulation of the TLR3/TICAM-1 pathway in vaccination? (2012)
  • Author(s): Tsukasa Seya, Masahiro Azuma, Hiroaki Shime, Misako Matsumoto
  • Organizer: Keystone Symposia
  • Place of Presentation: Ottawa, Canada
  • Year and Date: 2012-12-16
• [Presentation] Toll-like receptor 3を活性化するRNA構造の同定 (2012)
  • Author(s): 立松恵、瀬谷司、松本美佐子
  • Organizer: 第49回日本生化学会北海道支部例会
  • Place of Presentation: 札幌
  • Year and Date: 2012-07-20
• [Presentation] C-induced cross-priming and antitumor CTL depends on the TICAM-1 pathway in mouse Ag-presenting cells (2011)
  • Author(s): AZUMA Masahiro, EBIHARA Takashi, MATSUMOTO Misako, SEYA Tsukasa. PolyI
  • Organizer: 第40回日本免疫学会学術集会
  • Place of Presentation: 千葉
  • Year and Date: 20111127-29
• [Presentation] NC93B1 physically associates with human TLR8 and regulates TLR8-mediated signaling (2011)
  • Author(s): Megumi Tatematsu, Hiroki Itoh, Ayako Watanabe, Katsunori Iwano, Kenji Funami, Tsukasa Seya and Misako Matsumoto
  • Organizer: 第40回日本免疫学会学術集会
  • Place of Presentation: 千葉
  • Year and Date: 20111127-29
• [Presentation] Virus-derived single-stranded RNA with stable secondary structure extracellularly activates Toll-like receptor 3 (2011)
  • Author(s): Megumi Tatematsu, Tsukasa Seya, and Misako Matsumoto
  • Organizer: IUMS 2011 Congress
  • Place of Presentation: Sapporo, Japan
  • Year and Date: 20110911-16
• [Book] Endosome Signaling Part B, Vol 535, Assessment of the Toll-like receptor 3 pathway in endosomal signaling (2013)
  • Author(s): Matsumoto M., K. Funami, M. Tatematsu, M. Azuma, and T. Seya., (Edited by P. Michael Conn. Academic Press, ELSEVIER INC)
  • Total Pages: 149-165
  • Publisher: Methods Enzymol
• [Book] Jesus Giraldo, editors : Oligomerization in Health and Disease, Vol 117, PMBTS, UK, Toll-IL-1-receptor-containing adaptor molecule-1 (TICAM-1), a signaling adaptor linking innate immunity to adaptive immunity (2013)
  • Author(s): Matsumoto, M., K. Funami, H. Oshiumi, and T. Seya.
  • Total Pages: 485-510
  • Publisher: Academic Press