Study of mRNA translation in immune system

• Project/Area Number: 19H03488
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 49070:Immunology-related
• Research Institution: Kyoto University
• Principal Investigator: Mino Takahsi 京都大学, 医学研究科, 助教 (60646149)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥17,420,000 (Direct Cost: ¥13,400,000、Indirect Cost: ¥4,020,000); Fiscal Year 2021: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2020: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000); Fiscal Year 2019: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000)
• Keywords: 免疫 / サイトカイン / 転写後制御 / 翻訳 / mRNA分解 / Regnase-1 / UPF1 / 自然免疫 / リボソーム / mRNA

Outline of Research at the Start

本研究は，これまでの転写制御(mRNA産生の制御)と比較して未知の領域である，免疫システムにおけるmRNAの転写後制御機構(mRNAの局在，分解，翻訳)を解明することを目的としている。特に，近年，申請者らが免疫応答におけるmRNA制御に関わることを見出したRNA分解酵素Regnase-1，RNAヘリカーゼUPF1および蛋白質合成装置ribosomeに着目し，それらの制御因子を通じて免疫システムにおける新たなmRNAの翻訳制御機構の解明を試みる。

Outline of Final Research Achievements

Post-transcriptional regulation that modifies mRNA stability and translation provides rapid and flexible control of gene expression in immune system. Regnase-1-mediated mRNA decay (RMD), in which inflammatory mRNAs harboring specific stem-loop structures are degraded, is a critical part of proper immune homeostasis. However, the mechanisms of the RMD remain to be clarified. This study is aiming to investigate molecular mechanism of mRNA regulation and translation mediated by RMD. We found that Regnase-1 targets pioneer rounds of translation and is critical for rapid resolution of inflammation through restriction of the number of proteins translated by a given mRNA. Our findings reveal that RMD is essential for efficiently degrading inflammatory mRNAs undergoing pioneer rounds of translation.

Academic Significance and Societal Importance of the Research Achievements

炎症は，病原体の排除に重要な免疫反応であるが，過剰な炎症は敗血症性ショックや自己免疫疾患，動脈硬化，代謝性疾患など様々な病気の原因である。この炎症応答の厳密な制御にRNA制御が重要であることが近年明らかとなってきたが，その分子メカニズムは不明であった。本研究は，Regnase-1によるパイオニアラウンド翻訳が生じているmRNA分解が免疫制御に重要であることを解明した。本研究の成果は，過剰もしくは慢性的な炎症で生じる炎症性疾患の病態解明や，ワクチンの効果を高める添加剤(ワクチンアジュバント)の開発など，新たな治療法の開発につながることが期待される。

Research Products

• [Journal Article] Extracellular mRNA transported to the nucleus exerts translation-independent function (2021)
  • Author(s): Tomita Takeshi、Kato Masayoshi、Mishima Taishi、Matsunaga Yuta、Sanjo Hideki、Ito Ken-ichi、Minagawa Kentaro、Matsui Toshimitsu、Oikawa Hiroyuki、Takahashi Satoshi、Takao Toshifumi、Iwai Noriki、Mino Takashi、Takeuchi Osamu、Maru Yoshiro、Hiratsuka Sachie
  • Journal Title: Nature Communications Volume: 12 Issue: 1 Pages: 3655-3655
  • DOI: 10.1038/s41467-021-23969-1
  • Peer Reviewed / Open Access
• [Journal Article] Regnase‐1-related endoribonucleases in health and immunological diseases (2021)
  • Author(s): Mino Takashi、Takeuchi Osamu
  • Journal Title: Immunological Reviews Volume: 304 Issue: 1 Pages: 97-110
  • DOI: 10.1111/imr.13023
  • Peer Reviewed
• [Journal Article] IRAK1-dependent Regnase-1-14-3-3 complex formation controls Regnase-1-mediated mRNA decay (2021)
  • Author(s): Akaki Kotaro、Ogata Kosuke、Yamauchi Yuhei、Iwai Noriki、Tse Ka Man、Hia Fabian、Mochizuki Atsushi、Ishihama Yasushi、Mino Takashi、Takeuchi Osamu
  • Journal Title: eLife Volume: 10
  • DOI: 10.7554/elife.71966
  • NAID: 120007166024
  • Peer Reviewed / Open Access
• [Journal Article] Profibrotic function of pulmonary group 2 innate lymphoid cells is controlled by regnase-1 (2020)
  • Author(s): Nakatsuka Yoshinari、Yaku Ai、Handa Tomohiro、Vandenbon Alexis、Hikichi Yuki、Motomura Yasutaka、Sato Ayuko、Yoshinaga Masanori、Tanizawa Kiminobu、Watanabe Kizuku、Hirai Toyohiro、Chin Kazuo、Suzuki Yutaka、Uehata Takuya、Mino Takashi、Tsujimura Tohru、Moro Kazuyo、Takeuchi Osamu
  • Journal Title: European Respiratory Journal Volume: 57 Issue: 3 Pages: 2000018-2000018
  • DOI: 10.1183/13993003.00018-2020
  • Peer Reviewed
• [Journal Article] N4BP1 restricts HIV-1 and its inactivation by MALT1 promotes viral reactivation. (2019)
  • Author(s): Yamasoba D, Sato K, Ichinose T, Imamura T, Koepke L, Joas S, Reith E, Hotter D, Misawa N, Akaki K, Uehata T, Mino T, Miyamoto S, Noda T, Yamashita A, Standley DM, Kirchhoff F, Sauter D, Koyanagi Y, Takeuchi O.
  • Journal Title: Nat Microbiol Volume: 4 Issue: 9 Pages: 1532-1544
  • DOI: 10.1038/s41564-019-0460-3
  • NAID: 120006731123
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Translation-dependent unwinding of stem?loops by UPF1 licenses Regnase-1 to degrade inflammatory mRNAs (2019)
  • Author(s): Mino Takashi、Iwai Noriki、Endo Masayuki、Inoue Kentaro、Akaki Kotaro、Hia Fabian、Uehata Takuya、Emura Tomoko、Hidaka Kumi、Suzuki Yutaka、Standley Daron M、Okada-Hatakeyama Mariko、Ohno Shigeo、Sugiyama Hiroshi、Yamashita Akio、Takeuchi Osamu
  • Journal Title: Nucleic Acids Research Volume: 47 Pages: 8838-8859
  • DOI: 10.1093/nar/gkz628
  • NAID: 120006708220
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] RNA structure profiling reveals differential accessibility to regulatory RBPs in responses to immune stimulation (2021)
  • Author(s): 三野享史
  • Organizer: 第8 回CCR4-NOT研究会
• [Presentation] 炎症におけるRNA制御の分子基盤 (2021)
  • Author(s): 三野享史
  • Organizer: 第50回日本免疫学会学術集会
• [Presentation] Unwinding of stem-loops by UPF1 licenses Regnase-1 to degrade inflammatory mRNAs (2019)
  • Author(s): Mino Takashi、Takeuchi Osamu
  • Organizer: 第48回日本免疫学会学術集会
• [Presentation] Regnase-1による炎症性mRNA分解機構 (2019)
  • Author(s): 三野享史
  • Organizer: 第7回CCR4-NOT研究会
• [Remarks] 京都大学大学院医学研究科医化学分野竹内研究室HP
  • URL: https://mc.mfour.med.kyoto-u.ac.jp/index.html
• [Remarks] 炎症が制御される新たなメカニズムの解明
  • URL: https://www.kyoto-u.ac.jp/ja/research-news/2021-10-19-2
• [Remarks] 炎症が制御される新たなRNA分解メカニズムを解明 －新たな免疫賦活化法の開発に道筋－
  • URL: http://www.kyoto-u.ac.jp/ja/research/research_results/2019/190722_2.html