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Elucidation of the physiological and pathological roles of LINCR in innate immune response with a view to creating drugs to treat sepsis

Research Project

Project/Area Number 21H02691
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Review Section Basic Section 49010:Pathological biochemistry-related
Research InstitutionTohoku University

Principal Investigator

Noguchi Takuya  東北大学, 薬学研究科, 准教授 (20431893)

Project Period (FY) 2021-04-01 – 2024-03-31
Project Status Completed (Fiscal Year 2023)
Budget Amount *help
¥15,600,000 (Direct Cost: ¥12,000,000、Indirect Cost: ¥3,600,000)
Fiscal Year 2023: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000)
Fiscal Year 2022: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2021: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000)
Keywords自然免疫応答 / MAPキナーゼ / ユビキチン化酵素 / 炎症誘導 / Toll-like receptor / Toll-like receptor4 / MAP キナーゼ
Outline of Research at the Start

敗血症は、世界で年間約2700万人が罹患し、内800万人が臓器障害により死亡するという、現代社会が克服すべき重大な疾患である。しかし、未だ有効な治療法がなく、その克服は世界的に急務の課題となっている。我々は最近、LINCRというストレス応答分子が、敗血症の発症に大きく寄与しているのではないかという研究結果を得ている。そこで本研究では、敗血症治療薬の早出を見据え、LINCR欠損マウスを用いたin vivoでの解析を行い、LINCRの細菌感染症に対する生理的役割、および敗血症等におけるLINCRの病理的役割を解明する。

Outline of Final Research Achievements

Toll-like receptors (TLRs) drive innate immune responses via activation of intracellular signaling pathways, and play a pivotal role in host defense. Meanwhile, excessive activation of TLR signaling causes inflammatory disorders, including cytokine storm. Therefore, TLR signaling is properly controlled to balance optimal immune response and inflammation. However, its balancing mechanisms are not fully elucidated. We identified the E3 ubiquitin ligase LINCR/ NEURL3 as a TLR signal regulator. In LINCR-knockout cells, TLR-induced JNK and p38 MAPK activation was clearly attenuated. Consistent with these observations, TLR-induced production of a series of inflammatory cytokines was significantly reduced, indicating that LINCR positively regulates innate immune responses by promoting the JNK and p38 activation. Our further mechanistic study identified MAPK phosphatase-1 (MKP1), a negative regulator of MAP kinases, as a ubiquitination target of LINCR.

Academic Significance and Societal Importance of the Research Achievements

従来の抗炎症薬は、非特異的な免疫抑制による易感染性やホルモンバランスの異常による副腎不全等の重篤な副作用を発症することがある。我々は、LINCRというユビキチン化酵素が炎症誘導の強度や持続時間を調節している仕組みを解明し、LINCRが新たな炎症性疾患の治療標的として有用である可能性を示した。将来、LINCRを標的とした薬剤を開発することで、副作用の少ない抗炎症薬の開発につながる可能性がある。

Report

(4 results)
  • 2023 Annual Research Report   Final Research Report ( PDF )
  • 2022 Annual Research Report
  • 2021 Annual Research Report
  • Research Products

    (19 results)

All 2024 2023 2022 2021

All Journal Article (12 results) (of which Peer Reviewed: 12 results,  Open Access: 10 results) Presentation (7 results) (of which Int'l Joint Research: 4 results,  Invited: 4 results)

  • [Journal Article] The NLRP3 Inflammasome Is a Major Cause of Acute Renal Failure Induced by Polypeptide Antibiotics2024

    • Author(s)
      Kagi Tomohiro、Inoue Aya、Noguchi Takuya、Suzuki Wakana、Takano Saya、Otani Kohei、Naganuma Rio、Sekiguchi Yuto、Hirata Yusuke、Shindo Sawako、Hwang Gi-Wook、Matsuzawa Atsushi
    • Journal Title

      The Journal of Immunology

      Volume: - Issue: 11 Pages: 1807-1818

    • DOI

      10.4049/jimmunol.2300193

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed
  • [Journal Article] The E3 Ubiquitin Protein Ligase LINCR Amplifies the TLR-Mediated Signals through Direct Degradation of MKP12024

    • Author(s)
      Yokosawa Takumi、Miyagawa Sayoko、Suzuki Wakana、Nada Yuki、Hirata Yusuke、Noguchi Takuya、Matsuzawa Atsushi
    • Journal Title

      Cells

      Volume: 13 Issue: 8 Pages: 687-687

    • DOI

      10.3390/cells13080687

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Aggregability of the SQSTM1/p62-based aggresome-like induced structures determines the sensitivity to parthanatos2024

    • Author(s)
      Hamano Shuhei、Noguchi Takuya、Asai Yukino、Ito Ryo、Komatsu Ryuto、Sato Tetsu、Inoue Aya、Maruyama Tomoe、Kudo Tada-aki、Hirata Yusuke、Shindo Sawako、Uchida Yasuo、Hwang Gi-Wook、Matsuzawa Atsushi
    • Journal Title

      Cell Death Discovery

      Volume: 10 Issue: 1 Pages: 74-74

    • DOI

      10.1038/s41420-024-01838-2

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] LLPS of SQSTM1/p62 and NBR1 as outcomes of lysosomal stress response limits cancer cell metastasis2023

    • Author(s)
      Noguchi Takuya、Sekiguchi Yuto、Shimada Tatsuya、Suzuki Wakana、Yokosawa Takumi、Itoh Tamaki、Yamada Mayuka、Suzuki Midori、Kurokawa Reon、Hirata Yusuke、Matsuzawa Atsushi
    • Journal Title

      Proceedings of the National Academy of Sciences

      Volume: 120 Issue: 43 Pages: 44-44

    • DOI

      10.1073/pnas.2311282120

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] The NLRP3 Inflammasome Works as a Sensor for Detecting Hypoactivity of the Mitochondrial Src Family Kinases2023

    • Author(s)
      Sekiguchi Y, Takano S, Noguchi T, Kagi T, Komatsu R, Tan M, Hirata Y, Matsuzawa A
    • Journal Title

      J Immunol

      Volume: 210 Issue: 6 Pages: 795-806

    • DOI

      10.4049/jimmunol.2200611

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Reactive sulfur species disaggregate the SQSTM1/p62-based aggresome-like induced structures via the HSP70 induction and prevent parthanatos2023

    • Author(s)
      Yamada Yutaro、Noguchi Takuya、Suzuki Midori、Yamada Mayuka、Hirata Yusuke、Matsuzawa Atsushi
    • Journal Title

      Journal of Biological Chemistry

      Volume: in press Issue: 6 Pages: 104710-104710

    • DOI

      10.1016/j.jbc.2023.104710

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] The Distinct Roles of LKB1 and AMPK in p53-Dependent Apoptosis Induced by Cisplatin2022

    • Author(s)
      Shimada Tatsuya、Yabuki Yohsuke、Noguchi Takuya、Tsuchida Mei、Komatsu Ryuto、Hamano Shuhei、Yamada Mayuka、Ezaki Yusuke、Hirata Yusuke、Matsuzawa Atsushi
    • Journal Title

      International Journal of Molecular Sciences

      Volume: 23 Issue: 17 Pages: 10064-10064

    • DOI

      10.3390/ijms231710064

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] The polypeptide antibiotic polymyxin B acts as a pro-inflammatory irritant by preferentially targeting macrophages2022

    • Author(s)
      Kagi T, Naganuma R, Inoue A, Noguchi T, Hamano S, Sekiguchi Y, Hwang GW, Hirata Y, Matsuzawa A
    • Journal Title

      J Antibiot

      Volume: 75 Issue: 1 Pages: 29-39

    • DOI

      10.1038/s41429-021-00490-7

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Methylmercury induces neuronal cell death by inducing TNF-α expression through the ASK1/p38 signaling pathway in microglia2021

    • Author(s)
      Toyama Takashi、Hoshi Takayuki、Noguchi Takuya、Saito Yoshiro、Matsuzawa Atsushi、Naganuma Akira、Hwang Gi-Wook
    • Journal Title

      Scientific Reports

      Volume: 11 Issue: 1 Pages: 9831-9831

    • DOI

      10.1038/s41598-021-89210-7

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] trans-Fatty acids promote p53-dependent apoptosis triggered by cisplatin-induced DNA interstrand crosslinks via the Nox-RIP1-ASK1-MAPK pathway2021

    • Author(s)
      Hirata Y, Takahashi M, Yamada Y, Matsui R, Inoue A, Ashida R, Noguchi T, Matsuzawa A
    • Journal Title

      Sci Rep

      Volume: 11 Issue: 1 Pages: 10350-10350

    • DOI

      10.1038/s41598-021-89506-8

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] The E3 Ubiquitin-Protein Ligase RNF4 Promotes TNF-α-Induced Cell Death Triggered by RIPK12021

    • Author(s)
      Shimada T, Kudoh Y, Noguchi T, Kagi T, Suzuki M, Tsuchida M, Komatsu H, Takahashi M, Hirata Y, Matsuzawa A
    • Journal Title

      Int J Mol Sci

      Volume: 22 Issue: 11 Pages: 5796-5796

    • DOI

      10.3390/ijms22115796

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Mechanisms of gefitinib-induced interstitial pneumonitis: why and how the TKI perturbs innate immune systems?2021

    • Author(s)
      Kagi T, Noguchi T, Matsuzawa A
    • Journal Title

      Oncotarget

      Volume: 12 Issue: 13 Pages: 1321-1322

    • DOI

      10.18632/oncotarget.27958

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Presentation] 多機能分子p62/NBR1による液-液相分離(LLPS)を介した 新たな癌転移抑制機構2023

    • Author(s)
      野口拓也、松沢厚
    • Organizer
      フォーラム2023:衛生薬学・環境トキシコロジー
    • Related Report
      2023 Annual Research Report
    • Invited
  • [Presentation] 液-液相分離(LLPS)を介した新たな癌転移抑制機構2023

    • Author(s)
      野口拓也
    • Organizer
      Next Generation Symposium on Cell Signaling
    • Related Report
      2023 Annual Research Report
    • Invited
  • [Presentation] DNA 損傷応答におけるp62/SQSTM1液滴の役割2023

    • Author(s)
      野口拓也
    • Organizer
      第7回医薬品開発研究センターシンポジウム
    • Related Report
      2023 Annual Research Report
    • Invited
  • [Presentation] Involvement of the NLRP3 inflammasome in adverse drug reactions (ADRs)2021

    • Author(s)
      Takuya Noguchi, Atsushi Matsuzawa
    • Organizer
      THE 6TH JAPAN-TAIWAN JOINT SYMPOSIUM FOR PHARMACEUTICAL SCIENCES
    • Related Report
      2021 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] The E3 ubiquitin-protein ligase RNF4 promotes TNF-α-induced cell death triggered by RIPK12021

    • Author(s)
      Tatsuya Shimada, Tomohiro kagi, Midori Suzuki, Hiromu Komatsu, Yusuke Hirata, Takuya Noguchi, Atsushi Matsuzawa
    • Organizer
      環境衛生フォーラム2021日韓次世代ポスターセッション
    • Related Report
      2021 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Elucidation of the novel mechanisms by which gefitinib initiates inflammatory side effects2021

    • Author(s)
      Tomohiro Kagi , Yuto Sekiguchi, Saya Takano, Yusuke Hirata, Takuya Noguchi, and Atsushi Matsuzawa
    • Organizer
      International Graduate Student Conference in Pharmaceutical Sciences2021
    • Related Report
      2021 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Identification of the novel RING finger E3 ubiquitin ligase LINCR as a critical regulator of innate immune responses2021

    • Author(s)
      Takumi Yokosawa, Yusuke Hirata, Takuya Noguchi, and Atsushi Matsuzawa
    • Organizer
      International Graduate Student Conference in Pharmaceutical Sciences2021
    • Related Report
      2021 Annual Research Report
    • Int'l Joint Research

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Published: 2021-04-28   Modified: 2025-01-30  

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