2023 Fiscal Year Final Research Report
Comprehensive study on inflammatory and immune responses through complex linear ubiquitin code
| Project/Area Number |
21H02688
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Review Section |
Basic Section 48040:Medical biochemistry-related
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| Research Institution | Osaka Metropolitan University (2022-2023)
Osaka City University (2021) |
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Principal Investigator |
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| Project Period (FY) |
2021-04-01 – 2024-03-31
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| Keywords | タンパク質 / ユビキチン / 酵素 / 炎症 / 酸化ストレス / 細胞死 |
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| Outline of Final Research Achievements |
LUBAC is the only ubiquitin ligase (E3) that generates linear ubiquitin chains via the N-terminus Met1 of ubiquitin and regulates the NF-κB pathway and cell death, which are important for inflammation and immune responses. In this study, we identified OTUD1 as a deubiquitinating enzyme that strongly inhibits LUBAC-mediated NF-κB activation and LAP1 as an E3 that cooperates with LUBAC. OTUD1 not only regulates NF-κB but also regulates oxidative stress responses through KEAP1-binding, and mice lacking Otud1 were vulnerable to inflammatory bowel disease. LAP1 cooperated with LUBAC to control inflammatory cell death. This study showed ubiquitin dynamics centered on LUBAC are important for regulating inflammation, immunity, and cell death.
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| Free Research Field |
病態医化学
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| Academic Significance and Societal Importance of the Research Achievements |
本研究から、NF-κB経路や炎症性細胞死経路など細胞の生・死の制御にユビキチン修飾系が深く関わることが明らかになり、基礎生命科学、細胞生物学的に重要な学術的成果が得られた。OTUD1は酸化障害や病態とも深く関連することが示され、難病のクローン病や潰瘍性大腸炎に対する創薬標的となる可能性がある。2022年8月に発表したOTUD1に関するCell Death Dis論文は2024年5月段階で17回被引用、FWCI =2.73と良好なインパクトを与えている。また、LAP1はLUBACと協働して複雑型ユビキチン鎖生成を介して炎症性細胞死を制御するE3であり、今後の研究進展が期待できる。
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