Elucidation of the contribution of increased linear ubiquitin chain signaling to autoimmune diseases

2023 Fiscal Year Final Research Report

• Project/Area Number: 22K15379
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 48040:Medical biochemistry-related
• Research Institution: Kyoto University
• Principal Investigator: Fuseya Yasuhiro 京都大学, 医学研究科, 特定助教 (60866523)
• Project Period (FY): 2022-04-01 – 2024-03-31
• Keywords: LUBAC / HOIL-1L / 直鎖状ユビキチン鎖 / SLE / シェーグレン症候群 / NF-kappaB

Outline of Final Research Achievements

We showed that LUBAC ubiquitin ligase complex, which activates immune cells by generating linear ubiquitin chains is involved in the pathogenesis of systemic lupus erythematosus (SLE) and Sjogren's syndrome (SS). We had previously discovered that inhibition of the enzymatic activity of HOIL-1L, an accessory subunit of LUBAC, enhances LUBAC function.
We recently found that HOIL-1L enzyme deficiency in mice causes SLE and SS-like symptoms through enhanced linear ubiquitin chain formation, and that in humans, a single nucleotide variant (SNV) in the HOIL-1L gene that enhances LUBAC activity is significantly enriched in SLE patients. So, we identified HOIL-1L is a brand-new susceptibility gene for SLE.

Free Research Field

医学

Academic Significance and Societal Importance of the Research Achievements

マウス及びヒトの解析を駆使した本研究によって、LUBACの機能亢進による直鎖状ユビキチン鎖生成亢進が、炎症シグナルを活性化させることで、代表的な自己免疫疾患の一つであるSLEの発症に繋がることが明らかとなった。この結果はLUBACの機能を阻害することができればSLEの新規治療に繋がる可能性があることを示唆するものである。