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Study of UPF1-mediated mRNA regulation in immune system

Research Project

Project/Area Number 16K08832
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Immunology
Research InstitutionKyoto University

Principal Investigator

MINO Takashi  京都大学, ウイルス・再生医科学研究所, 助教 (60646149)

Research Collaborator TAKEUCHI Osamu  
Project Period (FY) 2016-04-01 – 2019-03-31
Project Status Completed (Fiscal Year 2018)
Budget Amount *help
¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2016: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
Keywords自然免疫 / サイトカイン / 転写後制御 / mRNA分解 / UPF1 / Regnase-1 / TTP / 翻訳 / mRNA安定性制御
Outline of Final Research Achievements

Post-transcriptional regulation that modifies mRNA stability and translation provides rapid and flexible control of gene expression and control of mRNA stability is important for coordinating the initiation and resolution of inflammation. However, the mechanisms of mRNA regulation in innate immune system remain to be clarified. This study is aiming to investigate the role of RNA helicase UPF1 in innate immune system. We generated LysM-Cre-UPF1Flox/Flox mice and found that UPF1 negatively regulated cytokine mRNAs such as IL6 and TNF by analyzing UPF1-deficient macrophages from LysM-Cre-UPF1Flox/Flox mice. Moreover, we found that UPF1 associated with Tristetraprolin (TTP), which is an RNA-binding protein and destabilize cytokine mRNAs such as TNF and CSF2 by targeting AU-rich elements in 3′ untranslated region, and UPF1 was required for the TTP-mediated mRNA decay. Our findings reveal that UPF1 plays a critical role in regulating cytokine mRNAs in innate immune system.

Academic Significance and Societal Importance of the Research Achievements

本研究により,UPF1はサイトカインmRNA制御に重要なRNAヘリカーゼであり,新たなmRNA制御メカニズムとして,UPFがTTPを介したmRNA制御に関わることを見出した。免疫応答制御には転写調節だけでなく,転写後調節によるmRNA安定性制御が重要な役割を果たしていることが近年明らかとなってきた。転写後調節による"ブレーキ"を失うとサイトカイン産生は劇的に増加し,自己免疫疾患を誘発し組織破壊や死亡へ繋がる。したがって,免疫応答における転写後調節の理解は炎症性疾患などの原因の解明や治療法の開発に繋がると期待される。本研究成果は,UPF1を標的とした新たな免疫制御法の開発に繋がると期待される。

Report

(4 results)
  • 2018 Annual Research Report   Final Research Report ( PDF )
  • 2017 Research-status Report
  • 2016 Research-status Report
  • Research Products

    (27 results)

All 2018 2017 2016 Other

All Journal Article (9 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 5 results,  Open Access: 2 results) Presentation (14 results) (of which Int'l Joint Research: 5 results,  Invited: 3 results) Remarks (3 results) Patent(Industrial Property Rights) (1 results)

  • [Journal Article] Post-transcriptional regulation of immune responses by RNA binding proteins2018

    • Author(s)
      MINO Takashi、TAKEUCHI Osamu
    • Journal Title

      Proceedings of the Japan Academy, Series B

      Volume: 94 Issue: 6 Pages: 248-258

    • DOI

      10.2183/pjab.94.017

    • NAID

      130007395766

    • ISSN
      0386-2208, 1349-2896
    • Year and Date
      2018-06-11
    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Pulmonary Regnase-1 orchestrates the interplay of epithelium and adaptive immune systems to protect against pneumonia2018

    • Author(s)
      Nakatsuka Yoshinari、Vandenbon Alexis、Mino Takashi、Yoshinaga Masanori、Uehata Takuya、Cui Xiaotong、Sato Ayuko、Tsujimura Tohru、Suzuki Yutaka、Sato Atsuyasu、Handa Tomohiro、Chin Kazuo、Sawa Teiji、Hirai Toyohiro、Takeuchi Osamu
    • Journal Title

      Mucosal Immunology

      Volume: AOP Issue: 4 Pages: 1203-1218

    • DOI

      10.1038/s41385-018-0024-5

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Regnase-1 Maintains Iron Homeostasis via the Degradation of Transferrin Receptor 1 and Prolyl-Hydroxylase-Domain-Containing Protein 3 mRNAs2017

    • Author(s)
      Yoshinaga Masanori、Nakatsuka Yoshinari、Vandenbon Alexis、Ori Daisuke、Uehata Takuya、Tsujimura Tohru、Suzuki Yutaka、Mino Takashi、Takeuchi Osamu
    • Journal Title

      Cell Reports

      Volume: 19 Issue: 8 Pages: 1614-1630

    • DOI

      10.1016/j.celrep.2017.05.009

    • NAID

      120006305989

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Regnase-1 and Roquin Nonredundantly Regulate Th1 Differentiation Causing Cardiac Inflammation and Fibrosis2017

    • Author(s)
      Cui Xiaotong、Mino Takashi、Yoshinaga Masanori、Nakatsuka Yoshinari、Hia Fabian、Yamasoba Daichi、Tsujimura Tohru、Tomonaga Keizo、Suzuki Yutaka、Uehata Takuya、Takeuchi Osamu
    • Journal Title

      The Journal of Immunology

      Volume: 199 Issue: 12 Pages: 4066-4077

    • DOI

      10.4049/jimmunol.1701211

    • Related Report
      2017 Research-status Report
    • Peer Reviewed
  • [Journal Article] NSD3 keeps IRF3 active2017

    • Author(s)
      Mino Takashi、Takeuchi Osamu
    • Journal Title

      The Journal of Experimental Medicine

      Volume: 214 Issue: 12 Pages: 3475-3476

    • DOI

      10.1084/jem.20171980

    • NAID

      120006534585

    • Related Report
      2017 Research-status Report
    • Peer Reviewed
  • [Journal Article] Regnase-1とRoquinによる炎症性mRNAの制御2016

    • Author(s)
      三野享史
    • Journal Title

      臨床免疫・アレルギー科

      Volume: 65 Pages: 180-184

    • NAID

      130005156510

    • Related Report
      2016 Research-status Report
  • [Journal Article] 免疫研究におけるRNA-Seq システム免疫学へのアプローチ2016

    • Author(s)
      三野享史, 竹内理
    • Journal Title

      実験医学別冊 NGSアプリケーション RNA-Seq実験ハンドブック

      Volume: NA Pages: 197-203

    • Related Report
      2016 Research-status Report
  • [Journal Article] Regnase-1とRoquinによる炎症性mRNAの制御2016

    • Author(s)
      三野享史, 竹内理
    • Journal Title

      医学のあゆみ

      Volume: 257 Pages: 180-182

    • NAID

      130005156510

    • Related Report
      2016 Research-status Report
  • [Journal Article] Regnase-1とRoquinによる炎症性mRNAの制御2016

    • Author(s)
      三野享史, 竹内理
    • Journal Title

      日薬理誌 特集

      Volume: 147 Pages: 351-356

    • NAID

      130005156510

    • Related Report
      2016 Research-status Report
  • [Presentation] The ribonuclease Regnase-1 maintains iron homeostasis via the destabilization of iron-regulatory transcripts2018

    • Author(s)
      Yoshinaga, M., Mino, T., and Takeuchi, O
    • Organizer
      RNA2018
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Regnase-1による炎症性mRNA分解機構2018

    • Author(s)
      三野享史
    • Organizer
      第6回CCR4-NOT研究会
    • Related Report
      2018 Annual Research Report
  • [Presentation] SMG1はRegnase-1経路を介して炎症性mRNAを制御する2018

    • Author(s)
      三野享史,岩井紀貴,赤木宏太朗,山下暁朗,竹内 理
    • Organizer
      第20回日本RNA学会年会
    • Related Report
      2018 Annual Research Report
  • [Presentation] 鉄代謝を制御する転写後調節機構の解明2018

    • Author(s)
      吉永正憲,三野享史,Bassik, M. C.,竹内理
    • Organizer
      第20回日本RNA学会年会
    • Related Report
      2018 Annual Research Report
  • [Presentation] Regnase-1は鉄代謝関連のmRNAを分解することで鉄恒常性を維持する2018

    • Author(s)
      吉永正憲,三野享史,竹内理
    • Organizer
      第41回日本分子生物学会年会
    • Related Report
      2018 Annual Research Report
  • [Presentation] SMG1はRegnase-1経路を介して炎症性mRNAを制御する2017

    • Author(s)
      三野享史,岩井紀貴,赤木宏太朗,山下暁朗,竹内 理
    • Organizer
      第19 回日本RNA学会年会
    • Related Report
      2017 Research-status Report
  • [Presentation] Regnase-1 regulates inflammation-related mRNAs during pioneer rounds of translation2017

    • Author(s)
      Takashi Mino, Osamu Takeuchi
    • Organizer
      第46回日本免疫学会学術集会
    • Related Report
      2017 Research-status Report
  • [Presentation] Post-transcriptional regulation of inflammation-related mRNAs by Regnase-12017

    • Author(s)
      Takashi Mino
    • Organizer
      The 12th International Symposium of the Institute Network -Driving Next-Generation Medicine: the Spirit of Pioneering Discovery in Medical Science-
    • Related Report
      2017 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] Post-transcriptional regulation of inflammation-related mRNAs by Regnase-1.2016

    • Author(s)
      Mino, T., and Takeuchi, O.
    • Organizer
      2016 Annual Meeting of Japanese Society for Immunology.
    • Place of Presentation
      Ginowan City, Japan
    • Year and Date
      2016-12-05
    • Related Report
      2016 Research-status Report
  • [Presentation] A pivotal role of Regnase-1 at the airway epithelium for the protection against pathogens through the enhancement of IgA secretion.2016

    • Author(s)
      Nakatsuka, Y., Mino, T., and Takeuchi, O.
    • Organizer
      2016 Annual Meeting of Japanese Society for Immunology.
    • Place of Presentation
      Ginowan City, Japan
    • Year and Date
      2016-12-05
    • Related Report
      2016 Research-status Report
  • [Presentation] The ribonuclease Regnase-1 plays a critical role in iron homeostasis and anemia.2016

    • Author(s)
      Yoshinaga, M., Mino, T., and Takeuchi, O.
    • Organizer
      2016 Annual Meeting of Japanese Society for Immunology.
    • Place of Presentation
      Ginowan City, Japan
    • Year and Date
      2016-12-05
    • Related Report
      2016 Research-status Report
  • [Presentation] Regnase-1 and Roquin regulate a common element in inflammatory mRNAs by spatiotemporally distinct mechanisms.2016

    • Author(s)
      Mino, T.
    • Organizer
      The 23rd East Asia Joint Symposium.
    • Place of Presentation
      Taipei City, Taiwan
    • Year and Date
      2016-10-18
    • Related Report
      2016 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] Post-transcriptional regulation of inflammation-related mRNAs by Regnase-1 and Roquin.2016

    • Author(s)
      Mino, T.
    • Organizer
      The 15th Awaji International Forum on Infection and Immunity.
    • Place of Presentation
      Awaji, Japan
    • Year and Date
      2016-09-06
    • Related Report
      2016 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] The ribonuclease Regnase-1 plays a role in iron homeostasis and anemia.2016

    • Author(s)
      Yoshinaga, M., Mino, T., and Takeuchi, O.
    • Organizer
      International Congress of Immunology 2016.
    • Place of Presentation
      Melbourne, Australia
    • Year and Date
      2016-08-21
    • Related Report
      2016 Research-status Report
    • Int'l Joint Research
  • [Remarks] 京都大学大学院医学研究科竹内研究室ホームページ

    • URL

      https://mc.mfour.med.kyoto-u.ac.jp/

    • Related Report
      2018 Annual Research Report
  • [Remarks] 京都大学ウイルス・再生医科学研究所竹内研究室ホームページ

    • URL

      http://www.infront.kyoto-u.ac.jp/ex_ivr/Lab/Takeuchi_HP/index.html

    • Related Report
      2017 Research-status Report
  • [Remarks] 京都大学ウイルス・再生医科学研究所竹内研究室ホームページ

    • URL

      http://www.virus.kyoto-u.ac.jp/Lab/Takeuchi_HP/index.html

    • Related Report
      2016 Research-status Report
  • [Patent(Industrial Property Rights)] SMG1阻害剤による免疫操作2017

    • Inventor(s)
      竹内理,三野享史,山下暁朗
    • Industrial Property Rights Holder
      竹内理,三野享史,山下暁朗
    • Industrial Property Rights Type
      特許
    • Industrial Property Number
      2017-199591
    • Filing Date
      2017
    • Acquisition Date
      2017
    • Related Report
      2017 Research-status Report

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Published: 2016-04-21   Modified: 2020-03-30  

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