Identification of deubiquitinases, which regulate inflammatory and immune signaling pathways, and screening for their inhibitors

2017 Fiscal Year Final Research Report

• Project/Area Number: 16K15210
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: General medical chemistry
• Research Institution: Osaka City University
• Principal Investigator: TOKUNAGA Fuminori 大阪市立大学, 大学院医学研究科, 教授 (00212069)
• Project Period (FY): 2016-04-01 – 2018-03-31
• Keywords: 酵素 / タンパク質 / 細胞・ 組織 / シグナル伝達 / 生体機能利用

Outline of Final Research Achievements

The deubiquitinating enzymes (DUBs) are proteases to antagonize ubiquitin modification system, and human genome encodes ~100 DUBs. In this study, we tried to identify DUBs, which regulate LUBAC- and linear ubiquitination-mediated NF-κB activation pathway. We found that HOIP is predominantly cleaved by caspase upon TNF-α-induced apoptosis. The N-terminal fragment of HOIP binds with DUBs, such as OTULIN and CYLD-SPATA2. In contrast, the C-terminal fragment of HOIP retains NF-κB activity, and linear ubiquitination of NEMO and FADD decreases upon apoptosis. These results indicate that caspase-mediated cleavage of HOIP divides critical functional regions of HOIP, and that this regulates linear (de)ubiquitination of substrates upon apoptosis.

Free Research Field

医化学一般