Analysis of interaction with synthesis and degradation in linear ubiquitin mediated NF-kappaB activation.

Research Project

Project/Area Number	26860188
Research Category	Grant-in-Aid for Young Scientists (B)
Allocation Type	Multi-year Fund
Research Field	General medical chemistry
Research Institution	Kyoto University
Principal Investigator	Nakagawa Tomoko 京都大学, 医学(系)研究科(研究院), 研究員 (90623976)
Project Period (FY)	2014-04-01 – 2016-03-31
Project Status	Completed (Fiscal Year 2015)
Budget Amount *help	¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000) Fiscal Year 2015: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000) Fiscal Year 2014: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
Keywords	シグナル伝達 / NF-kappaB / ユビキチン
Outline of Final Research Achievements	I have shown that OTULIN and CYLD, which are deubiquitinating enzymes (DUBs) cleaving linear ubiquitin chains specifically, down-regulate NF-κB activation by binding to HOIP, a subunit of LUBAC. Based on my original findings, I dissected the physiological roles of coordinated synthesis and cleavage of linear ubiquitination by co-existing its ligase and DUBs in this research proposal. Using OTULIN conditional knockout mice, I have dissected the roles of coordinated synthesis and cleavage of linear ubiquitination in B and T lymphocytes. To my disappointment, I could not found any abnormality in OTULIN null T or B cells. However, in collaboration with the research group in Hokkaido University, I start dissecting the molecular mechanisms underlying hyper-inflammatory symptoms found in a patient having mutations in OTULIN genes and found that inflammation provoked by pathogens could not be terminated because of the attenuated DUB activity of OTULIN.