Analysis of immunoproteasome function in immune cell development

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K06956
• 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
• Principal Investigator: Hemmi Hiroaki 岡山理科大学, 獣医学部, 教授 (20451924)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: プロテアソーム / 免疫担当細胞分化 / モデルマウス

Outline of Final Research Achievements

The proteasome is a large protein complex degrading intracellular protein, and plays important roles in maintenance of cellular homeostasis including intracellular signal transduction and processing of antigen peptides. Genetic variation(s) in proteasome subunit genes might lead to severe autoinflammatory diseases, called proteasome-associated autoinflammatory syndrome (PRAAS). In this study, we analyzed mutant mice carrying a genetic variant in a proteasome subunit gene identified in PRAAS-like patients. We found that heterozygous mutant mice showed reduced lymphocytes and increased myeloid cells. In homozygous mice, lymphocytes and dendritic cells were hardly detected, and lymphoid biased multipotent progenitors were also affected. These results suggest that proteasome function is important for immune cell development. Thus, this model mouse is useful to analyzing pathological and physiological function of proteasome in hematopoiesis 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、様々な細胞や組織における恒常性の維持などに関与しており、その異常は炎症性疾患やがんなど多様な疾患でも報告されている。そのため、プロテアソームサブユニット遺伝子に生じたバリアントにより発症するプロテアソーム関連自己炎症候群について、その病態や分子基盤を解明することは、当該疾患だけでなく多様な疾患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遺伝子バリアントを導入したマウスを解析した。本モデルマウスの解析により、プロテアソームの生理的機能の解明に加え、炎症病態等の新たなメカニズム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。