Roles of p97/VCP in linear ubiquitin mediated NF-kappaB activation

• Project/Area Number: 24790279
• 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): 2012-04-01 – 2014-03-31
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2013: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2012: ¥2,860,000 (Direct Cost: ¥2,200,000、Indirect Cost: ¥660,000)
• Keywords: PUBドメイン / LUBAC / 直鎖状ポリユビキチン鎖 / NF-kappaB

Research Abstract

The LUBAC ubiquiin ligase is composed of three subunits, HOIP, HOIL-1L and SHARPIN. LUBAC possesses multiple domains, but the role of the PUB domain that exists in the N-terminal region of HOIP had not been addressed. The PUB domain has been identified as a binding domain of p97/VCP. Since p97/VCP has shown to regulate NF-kappaB activation negatively, we examined the role of the PUB domain in LUBAC mediated NF-kappaB activation. To our surprise, in cells expressing a HOIP mutant, which cannot bind p97/VCP, both NF-kappaB activation and linear polyubiquitination of NEMO mediated by TNF-alpha were augmented. We then sought proteins bound to the PUB domain of HOIP and found that two deubiquitinases, OTULIN and CYLD, that specifically cleaved linear chains as interacting proteins of HOIP PUB. Both OTULIN and CYLD bind to the PUB domain of HOIP directly and down-regulated LUBAC-mediated NF-kappaB activation.

Research Products

• [Journal Article] Suppression of LUBAC-mediated linear ubiquitination by a specific interaction between LUBAC and the deubiquitinases CYLD and OTULIN (2014)
  • Author(s): Takiuchi T, Nakagawa T, Tamiya H, Fujita H, Sasaki Y, Saeki Y, Takeda H, Sawasaki T, Buchberger A, Kimura T, and Iwai K
  • Journal Title: Genes Cells Volume: 19 Pages: 254-272
• [Journal Article] Suppression of LUBAC-mediated linear ubiquitination by a specific interaction between LUBAC and the deubiquitinases CYLD and OTULIN. (2014)
  • Author(s): Takiuchi, T., Nakagawa, T., Tamiya, H., Fujita, H., Sasaki, Y., Saeki, Y., Takeda, H., Sawasaki, T., Buchberger, A., Kimura, T., and Iwai. K.
  • Journal Title: Genes Cells. Volume: 19 Issue: 3 Pages: 254-272
  • DOI: 10.1111/gtc.12128
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Remarks] 京都大学・大学院医学研究科・細胞機能制御学
  • URL: http://www.mcp.med.kyoto-u.ac.jp/