Molecular mechanisms for the detection of microbes and cancer cells in innate immunity

2012 Fiscal Year Final Research Report

• Project/Area Number: 20679003
• Research Category: Grant-in-Aid for Young Scientists (S)
• Allocation Type: Single-year Grants
• Research Field: Immunology
• Research Institution: Hokkaido University
• Principal Investigator: TAKAOKA Akinori 北海道大学, 遺伝子病制御研究所, 教授 (30323611)
• Project Period (FY): 2008 – 2012
• Keywords: パターン認識受容体 / 核酸 / 感染 / がん / 生体防御 / ウイルス / PARP

Research Abstract

In this project, we tried to elucidate a regulatory mechanism for the activation of PRRs, particularly nucleic acid sensors, and the related signaling pathways, leading to the induction of cytokine/chemokine genes in innate immune responses for host defense against viral infection and cancer. First, we found that the poly(ADP-ribose) polymerase (PARP)-13 shorter isoform (ZAPS) critically functions as a potent stimulator of IFN responses in human cells mediated by RIG-I, through the physical association of ZAPS with RIG-I. Next, we revealed that ZAPS is a factor targeted by Influenza viral NS1 protein for viral innate immune evasion. In addition, we showed a role of PARP-7/TIPARP and PARP-12 as a possible negative regulator of RIG-I-meditated innate immune signalings. Furthermore, we also identified a candidate DNA sensor for human cytomegalovirus (HCMV). On the other hand, this project contributed to the research, wherein it has been shown a novel mechanism for the suppression of innate immune signalings mediated by tumor-derived DNA in tumor-infiltrating dendritic cells. These results may provide a therapeutic and preventive insight for the control of viral infection and cancer.

Research Products

• [Journal Article] Targeted induction of interferon- λ in humanized chimeric mouse liver abrogates hepatotropic virus infection. (2013)
  • Author(s): Nakagawa S, Hirata Y, Kameyama T, Tokunaga Y, Nishito Y, Hirabayashi K, Yano J, Ochiya T, Tateno C, Tanaka Y, MizokamiM, Tsukiyama-Kohara K, Inoue K, Yoshiba M, Takaoka A, Kohara M
  • Journal Title: PLoS One Volume: 8(3) Pages: 59611
  • Peer Reviewed
• [Journal Article] Tumor-infiltrating DCs suppress nucleic acid-mediated innate immune responses through interactions between the receptor TIM-3 and the alarmin HMGB1 (2012)
  • Author(s): Chiba S, Baghdadi M, Akiba H, Yoshiyama H, Kinoshita I, Dosaka-Akita H, Fujioka Y, Ohba Y, Gorman JV, Colgan JD, Hirashima M, Uede T, Takaoka, A, Yagita H, Jinushi M
  • Journal Title: Nat Immunol Volume: 13(9) Pages: 832-842
  • Peer Reviewed
• [Journal Article] ATM-mediated DNA damage signals mediate immune escape through integrin αvβ3-dependent mechanisms (2011)
  • Author(s): Jinushi, M., Chiba, S., Baghdadi, M., Kinoshita, I., Dosaka-Akita, H., Ito, K., Yoshiyama, H., Yagita, H., Uede, T., Takaoka, A
  • Journal Title: Cancer Res Volume: 72 Pages: 56-65
  • Peer Reviewed
• [Journal Article] Tumor-associated macrophages regulate tumorigenicity and anticancer drug responses of cancer stem/initiating cells (2011)
  • Author(s): Jinushi, M., Chiba, S., Yoshiyama, H., Masutomi, K., Kinoshita, I., Dosaka-Akita, H., Yagita, H., Takaoka, A., Tahara, H
  • Journal Title: Proc. Natl. Acad. Sci. U S A Volume: 108 Pages: 12425-30
  • Peer Reviewed
• [Journal Article] Interferon-α/ss and anti-fibroblast growth factor receptor 1 monoclonal antibody suppress hepatic cancer cells in vitro and in vivo (2011)
  • Author(s): Sasaki, S., Ishida, T., Toyota, M., Ota, A., Suzuki, H., Takaoka, A., Yasui, H., Yamamoto, H., Takagi, H., Maeda, M., Seito, T., Tsujisaki, M., Shinomura, Y., Imai, K
  • Journal Title: PLoS One Volume: 6 Pages: 19618
  • Peer Reviewed
• [Journal Article] IRF3 regulates cardiac fibrosis butnot hypertrophy in mice during angiotensinII-induced hypertension (2011)
  • Author(s): Tsushima, K., Osawa, T., Yanai, H., Nakajima, A., Takaoka, A., Manabe, I., Ohba, Y., Imai, Y., Taniguchi, T., Nagai, R
  • Journal Title: FASEB J Volume: 25 Pages: 1531-1543
  • Peer Reviewed
• [Journal Article] ZAPS is a potent stimulator of signaling mediated by the RNA helicase RIG-I during antiviral responses (2011)
  • Author(s): Hayakawa, S., Shiratori, S., Yamato, H., Kameyama, T., Kitatsuji, C., Kashigi, F., Goto, S., Kameoka, S., Fujikura, D., Yamada, T., Mizutani, T., Kazumata, M., Sato, M., Tanaka, J., Asaka, M., Ohba, Y., Miyazaki, T., Imamura, M., and Takaoka, A
  • Journal Title: Nat. Immunol Volume: 12 Pages: 37-44
  • Peer Reviewed
• [Journal Article] Critical role for constitutive type I interferon signaling in the prevention of cellular transformation (2009)
  • Author(s): Chen, H.M., Tanaka, N., Mitani, Y., Oda,E., Nozawa, H., Chen, J.Z., Yanai, H., Negishi, H., Choi, M.K., Iwasaki, T., Yamamoto, H., Taniguchi, T., and Takaoka, A.
  • Journal Title: Cancer Sci Volume: 100 Pages: 449-456
  • Peer Reviewed
• [Presentation] Helicobacter pylori pathogenic facter CagA dependent induction of interleukin-1 ss from macrophages (2012)
  • Author(s): 高岡晃教
  • Organizer: 日本免疫学会
  • Place of Presentation: 神戸国際会議場
  • Year and Date: 20121205-07
• [Presentation] ZAPS potentiates RIG-I signaling to drive type IFN production for antiviral response (2012)
  • Author(s): Takaoka, A
  • Organizer: ICAR2012
  • Place of Presentation: Universidade de Lisboa(ポルトガル)
  • Year and Date: 20121120-24
• [Presentation] Nucleic acid sensors for detecting viral infection (2012)
  • Author(s): Takaoka, A
  • Organizer: IEIIS2012Homeostatic Inflammation Symposium
  • Place of Presentation: 学術総合センター
  • Year and Date: 20121023-26
• [Presentation] ZAPS functions as an antiviral regulator in innate immunity (2012)
  • Author(s): Takaoka, A
  • Organizer: Istanbul International Immunology Forum
  • Place of Presentation: CROWNE PLAZA ISTANBUL-OLD CITY HOTEL (イスタンブール)
  • Year and Date: 20120301-02
• [Presentation] Zaps as a booster of innate immune signaaling for antviral defense against influenza virus infection (2012)
  • Author(s): Takaoka, A
  • Organizer: 4th INTERNATIONAL CONFERENCE ON DRUG DISCOVERY & THERAPY
  • Place of Presentation: Dubai Mens College (ドバイ)
  • Year and Date: 2012-02-12
• [Presentation] Roles of ZAPS as an antiviral regulator in innate immunity (2011)
  • Author(s): Takaoka, A
  • Organizer: 2nd CSI/JSI/KAI Joint Symposium onImmunology
  • Place of Presentation: 千里阪急ホテル
  • Year and Date: 20111204-06
• [Presentation] Identification of a novel regulator of the innate signalingactivated by virus-derived nucleic acids (2010)
  • Author(s): Takaoka, A
  • Organizer: 2010 annual meeting of the french society for immunology
  • Place of Presentation: Palais du Pharo (フランス)
  • Year and Date: 2010-11-25
• [Presentation] Innate immune signaling and cancer (2010)
  • Author(s): 高岡晃教
  • Organizer: 第71回日本癌学会学術総会
  • Place of Presentation: ホテルロイトン札幌
  • Year and Date: 2010-09-21
• [Presentation] Regulation of cytosolic nucleic acid-activated innate responses by the IFN-inducible protein SCI2 (2010)
  • Author(s): Takaoka, A
  • Organizer: The14th International Congress of Immunology
  • Place of Presentation: 神戸国際展示場
  • Year and Date: 2010-08-25
• [Presentation] A Novel Regulator of the Innate Signaling Activated by Cytoplasmic Nucleic Acids (2010)
  • Author(s): Takaoka, A
  • Organizer: BIT's 1st World Congress Of Virus and Infections-2010
  • Place of Presentation: Busan Exhibition & Convention Center (韓国)
  • Year and Date: 2010-07-31
• [Presentation] 自然免疫におけるIFN応答の新たな制御メカニズム (2009)
  • Author(s): 高岡晃教
  • Organizer: 第32回日本分子生物学会年会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2009-12-10
• [Presentation] 核酸を介する自然免疫活性化機構の解析 (2009)
  • Author(s): 高岡晃教
  • Organizer: 第39回日本免疫学会総会・学術集会
  • Place of Presentation: 大阪国際会議場
  • Year and Date: 2009-12-03
• [Presentation] SCI2を介した自然免疫応答制御 (2009)
  • Author(s): 高岡晃教
  • Organizer: 第82回日本生化学会大会
  • Place of Presentation: 神戸ポートアイランド
  • Year and Date: 2009-10-24
• [Presentation] Novel function of DNA triggered innate immune responses (2008)
  • Author(s): Takaoka, A
  • Organizer: The 8th Awaji International Forum on Infection and Immunity
  • Place of Presentation: 淡路島夢舞台国際会議場
  • Year and Date: 20080902-05
• [Presentation] DNA Sensing Mechanism for the Activation of Innate Immune Responses (2008)
  • Author(s): Takaoka, A
  • Organizer: BIT's 2nd World Congress of Gene 2008
  • Place of Presentation: Foshan Sanshui Garden Hotel (中国)
  • Year and Date: 2008-12-06
• [Presentation] DNA-mediated activation of innate of immune responses; itspossible involvement in turmor immunity (2008)
  • Author(s): Takaoka, A
  • Organizer: BIT's 1st Annual World Vaccine Congress2008
  • Place of Presentation: Foshan Sanshui GardenHotel (中国)
  • Year and Date: 2008-12-03
• [Presentation] Activation of Innate Immune Response Mediated by DNA-triggered Danger Signals (2008)
  • Author(s): Takaoka, A
  • Organizer: The 36th Congress of the International Society of Oncology &BioMarkers
  • Place of Presentation: インターコンチネンタル東京ベイ
  • Year and Date: 2008-10-06
• [Book] 分子標的薬,NF-κB シグナル経路と炎症 (2012)
  • Author(s): 山田大翔,高岡晃教
  • Total Pages: 225-230
  • Publisher: 日本臨牀社
• [Book] 分子標的薬,IFN と受容体を介するシグナル経路 (2012)
  • Author(s): 中村亨,高岡晃教
  • Total Pages: 181-185
  • Publisher: 日本臨牀社
• [Book] 臨床免疫・アレルギー科 (2012)
  • Author(s): 亀山武志,中村亨,高岡晃教
  • Total Pages: 216-226
  • Publisher: 科学評論社
• [Book] 自然免疫系における核酸認識機構-核酸センサーRIG-Iと制御因子ZAPS (2011)
  • Author(s): 高岡晃教,山田大翔,林真寛
  • Total Pages: 80-91
  • Publisher: 生物の科学遺伝
• [Book] 自己炎症疾患の新しい知見総説パターン認識受容体-Pattern recognition receptors- (2011)
  • Author(s): 高岡晃教,中村亨,林隆也
  • Total Pages: 329-345
  • Publisher: Jpn. J. Clin. Immunol
• [Book] 感染・炎症・免疫,RIG-Iシグナルの正の制御因子"ZAPS" (2011)
  • Author(s): 太宰昌佳,高岡晃教
  • Publisher: 医薬の門社
• [Book] 生体の化学,自然免疫系におけるDNAセンサーとインムラマソーム (2011)
  • Author(s): 高岡晃教,鈴木絵里加,浦山優輔,木口舞美
  • Total Pages: 188-201
  • Publisher: 金原一郎記念医学医療振興財団/医学書院
• [Book] 疾患モデルの作製と利用-免疫疾患,第3章第3節第2項 (2011)
  • Author(s): 高岡晃教,亀山武志,亀岡章一郎
  • Total Pages: 405-441
  • Publisher: IRFファミリー
• [Book] 自然免疫系における核酸センサーとサイトカイン誘導経路 (2010)
  • Author(s): 高岡晃教,浦山優輔,鈴木絵里加
  • Total Pages: 34-47
  • Publisher: 実験医学
• [Book] DAI(DNA依存性IRF活性化因子;DNA-dependent activator of interferon-regulatory factors;別名DLM-1/ZBP1) (2009)
  • Author(s): 高岡晃教
  • Total Pages: 237
  • Publisher: 「生化学」誌
• [Book] 自然免疫における核酸センサー分子 (2008)
  • Author(s): 高岡晃教,樫木芙美,後藤翔平,数馬田美香
  • Total Pages: 165-181
  • Publisher: 「生化学」誌
• [Book] 分子細胞治療,用語解説より「DAI」 (2008)
  • Author(s): 白鳥聡一,高岡晃教
  • Total Pages: 62-66
  • Publisher: 先端医学社
• [Book] ゲノム医学,自然免疫とウイルス感染 (2008)
  • Author(s): 高岡晃教,大和弘明
  • Total Pages: 27-42
  • Publisher: メディカルレビュー社
• [Book] IFN,サイトカイン-2 がん治療の分子標的となる IFN-IRF系のシグナル伝達分子 (2008)
  • Author(s): 高岡晃教,佐藤昇志,宮崎忠昭,南山堂
  • Total Pages: 358-362
  • Publisher: がんの分子標的治療
• [Book] 臨床免疫・アレルギー科,自然免疫のDNA認識機構とそのセンサー分子 (2008)
  • Author(s): 高岡晃教,後藤翔平,樫木芙美
  • Total Pages: 723-732
  • Publisher: 化学評論社
• [Remarks]
  • URL: http://www.igm.hokudai.ac.jp/sci/