Study of UPF1-mediated mRNA regulation in immune system

2018 Fiscal Year Final Research Report

• Project/Area Number: 16K08832
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Immunology
• Research Institution: Kyoto 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
• 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

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.

Free Research Field

免疫学

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。