A novel mechanism for regulation of mRNA stability through functional inactivation of Regnase-1.

2022 Fiscal Year Final Research Report

• Project/Area Number: 20H03502
• 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: Osaka University
• Principal Investigator: Hiroki Tanaka 大阪大学, 免疫学フロンティア研究センター, 特任講師(常勤) (50747920)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: mRNA安定性 / 蛋白質リン酸化 / 蛋白質分解

Outline of Final Research Achievements

In this research project, we focus on the functional inactivation of the endoribonuclease Regnase-1, which enzymatic activity is transiently lost through it phosphorylation and proteolysis. To address the mechanism by which the functional inactivation mediates innate and acquired immunity, we used Regnase-1 ΔCTD mice, carrying the C-terminal truncated mutation of Regnase-1 protein that completely inhibits Regnase-1 phosphorylation. This mutation is known to have a strong inhibitory effect on innate immune response primed by external stimuli with inflammatory cytokines or TLR ligands. Contrary to our expectation, this mutation showed activation of a group of immune cells such as antigen-presenting cells and was found to exacerbate disease phenotypes of mutated mice that develop spontaneous autoimmunity. The findings obtained in this project will greatly contribute to the elucidation of the functional role of Regnase-1 as a therapeutic target for diseases.

Free Research Field

免疫学

Academic Significance and Societal Importance of the Research Achievements

Regnase-1蛋白質はmRNA分解によって免疫機能を制御するという、他の免疫細胞と一線を画するユニークな性質を有している。また、この蛋白質は外部からの刺激に対して鋭敏に応答して不活性化することで様々な免疫反応を制御しているが、この蛋白質の機能不活性化を阻害することで強力な抗炎症効果が得られることが知られている。今回得られた知見は、Regnase-1の持つ新たな免疫制御作用の一端の解明に貢献しており、Regnase-1蛋白質の持つ機能のより深い理解につながり、Regnase-1を標的とした創薬応用においても多いに役立つのではないかと我々は考えている。