Project/Area Number |
15H04694
|
Research Category |
Grant-in-Aid for Scientific Research (B)
|
Allocation Type | Single-year Grants |
Section | 一般 |
Research Field |
General medical chemistry
|
Research Institution | Osaka City University (2016-2017) Gunma University (2015) |
Principal Investigator |
|
Co-Investigator(Renkei-kenkyūsha) |
SAWASAKI Tatsuya 愛媛大学, プロテオサイエンスセンター, 教授 (50314969)
|
Project Period (FY) |
2015-04-01 – 2018-03-31
|
Project Status |
Completed (Fiscal Year 2017)
|
Budget Amount *help |
¥17,290,000 (Direct Cost: ¥13,300,000、Indirect Cost: ¥3,990,000)
Fiscal Year 2017: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000)
Fiscal Year 2016: ¥6,240,000 (Direct Cost: ¥4,800,000、Indirect Cost: ¥1,440,000)
Fiscal Year 2015: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000)
|
Keywords | 酵素 / タンパク質 / 細胞・ 組織 / シグナル伝達 / 炎症 / 蛋白質 / 細胞・組織 / 免疫学 / 生理活性 |
Outline of Final Research Achievements |
We identified LUBAC ubiquitin ligase complex, which specifically generates the N-terminal Met(M)1-linked linear polyubiquitin chain, and LUBAC is involved in the NF-κB activation pathway to regulate innate immune and inflammatory responses. In this study, we focused on optineurin (OPTN), a linear ubiquitin-binding and NF-κB-suppressive protein. Wild-type OPTN down-regulates NF-κB activation and apoptosis, whereas OPTN mutants which cause amyotrophic lateral sclerosis (ALS) failed to suppress these cellular functions due to the lack of linear ubiquitin binding ability. Furthermore, immunohistochemical analyses of motor neurons from OPTN-associated ALS patients revealed that linear ubiquitin and activated NF-κB partially colocalized with cytoplasmic inclusions. Taken together, OPTN regulates both NF-κB activation and apoptosis via linear ubiquitin-binding, and the loss of this ability may lead to ALS by sustained neuroinflammation and enhanced apoptosis.
|