Analysis of the immunoproteasome function in innate immunity

2020 Fiscal Year Final Research Report

• Project/Area Number: 18K07071
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 49030:Experimental pathology-related
• Research Institution: Okayama University of Science (2019-2020); Wakayama Medical University (2018)
• Principal Investigator: Hemmi Hiroaki 岡山理科大学, 獣医学部, 教授 (20451924)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Keywords: プロテアソーム / 自然免疫 / 樹状細胞 / 単球

Outline of Final Research Achievements

The proteasome is a large protein complex involved in degradation of intracellular proteins, and plays important roles in not only maintenance of cellular homeostasis by degrading damaged and/or useless proteins, but also intracellular signal transduction and generation of antigen peptides. Genetic mutation in several proteasome subunit genes cause severe autoinflammatory diseases, called proteasome-associated autoinflammatory syndrome (PRAAS). However, its pathological mechanisms are largely unveiled. In this study, mutant mice, carrying a novel mutation found in a proteasome subunit gene from PRAAS-like patients, were analyzed. We found that the mutation affected monocyte and dendritic cell differentiation, in addition to impaired lymphocyte development and/or functions. This mutant mouse model is useful for analyzing physiological function of proteasome on innate immune cell differentiation as well as its pathological functions in PRAAS.

Free Research Field

免疫学

Academic Significance and Societal Importance of the Research Achievements

プロテアソームは、様々な細胞や組織の恒常性の維持だけでなく、がんや炎症など多彩な疾患にも関与している。プロテアソームを構成する分子に生じた遺伝子変異により発症するプロテアソーム関連自己炎症性疾患についてその病態を解明することは、当該疾患だけでなく、一般的な炎症病態の治療法の開発にも有用であると考えられる。本研究では、当該疾患患者由来の新規遺伝子変異を導入したマウスを解析し、これまで知られていなかった骨髄系細胞の分化障害を見いだした。本変異マウスの解析により、プロテアソームの生理的機能および炎症病態の新たなメカニズムが解明や新規の炎症病態制御剤の開発につながる成果が得られることが期待される。