Underlying mechanisms for immune disorders caused by proteasome dysfunctions

2022 Fiscal Year Final Research Report

• Project/Area Number: 21K19384
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 49:Pathology, infection/immunology, and related fields
• Research Institution: Wakayama Medical University
• Principal Investigator: Kaisho Tsuneyasu 和歌山県立医科大学, 先端医学研究所, 教授 (60224325)
• Co-Investigator(Kenkyū-buntansha): 金澤 伸雄 兵庫医科大学, 医学部, 教授 (90343227)
• Project Period (FY): 2021-07-09 – 2023-03-31
• Keywords: プロテアソーム / タンパク質分解 / 自己炎症 / 免疫不全

Outline of Final Research Achievements

A novel heterozygous missense variant (p.G156D variant) was commonly detected in the gene encoding the proteasome subunit beta1i in two patients showing autoinflammatory manifestations with acquired immune deficiency. This variant was introduced into mice and analyzed. In the heterozygous mutant mice, acquired immunodeficiency was reproduced and, concerning the innate immune cells, monocytes and neutrophils were increased in number. The results led us to propose a new disease category, proteasome-associated autoinflammatory syndrome with immunodeficiency.

Free Research Field

免疫学

Academic Significance and Societal Importance of the Research Achievements

プロテアソームサブユニットの新規の遺伝子バリアントが同定され、そのバリアントを持つマウスにおいてヒト病態が再現された。プロテアソームの機能異常は、稀少疾患ばかりでなく、がん、神経変性、老化などcommon diseaseにおいてもみとめられる。本研究で樹立された遺伝子改変マウスの更なる解析により、プロテアソーム機能異常により生じる様々な病態解明が進むことが期待される。