Screening for interactors of linear ubiquitin chain assembly complex (LUBAC), and studies on their physiological functions

2017 Fiscal Year Final Research Report

• 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: TOKUNAGA Fuminori 大阪市立大学, 大学院医学研究科, 教授 (00212069)
• 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
• Keywords: 酵素 / タンパク質 / 細胞・ 組織 / シグナル伝達 / 炎症

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.

Free Research Field

医化学一般