Analysis of functions of LUBAC in B1 cell development

• Project/Area Number: 17K08880
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Immunology
• Research Institution: Tohoku Medical and Pharmaceutical University (2018-2020); Kyoto University (2017)
• Principal Investigator: Sasaki Yoshiteru 東北医科薬科大学, 医学部, 助教 (80323004)
• Project Period (FY): 2017-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2017: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 免疫学 / シグナル伝達 / 発生・分化

Outline of Final Research Achievements

Linear polyubiquitin chains are generated specifically by the ubiquitin ligase complex LUBAC. LUBAC is composed of one catalytic subunit, HOIP and two accessary subunits, HOIL-1L and SHARPIN. Linear polyubiquitin chains are known to play important roles in activation of NF-κB and inhibition of programed cell death including apoptosis and necroptosis by TNF stimulation. In this study I analyzed the role of LUBAC in B1 cell development. B1 cells are subdivided into B1a (CD5+) and B1b (CD5-) cells according to CD5 expression. LUBAC is required for the development of both B1a and B1b cells. In this study I found that deletion of RIP3, a critical regulator of necroptosis rescued the development of B1b cells but not B1a cells. This data shows that LUBAC controls B1a and B1b cell development in a different manner.

Academic Significance and Societal Importance of the Research Achievements

本研究の学術的意義としては、これまで不明な点が多かったB1a細胞とB1b細胞の発生機構の違いを明らかにした点が挙げられる。

Research Products

• [Journal Article] LUBAC accelerates B-cell lymphomagenesis by conferring resistance to genotoxic stress on B cells (2020)
  • Author(s): Jo Tomoyasu、Nishikori Momoko、Kogure Yasunori、Arima Hiroshi、Sasaki Katsuhiro、Sasaki Yoshiteru、Nakagawa Tomoko、Iwai Fumie、Momose Shuji、Shiraishi Aki、Kiyonari Hiroshi、Kagaya Noritaka、Onuki Tetsuo、Shin-ya Kazuo、Yoshida Minoru、Kataoka Keisuke、Ogawa Seishi、Iwai Kazuhiro、Takaori-Kondo Akifumi
  • Journal Title: Blood Volume: 136 Issue: 6 Pages: 684-697
  • DOI: 10.1182/blood.2019002654
  • Peer Reviewed / Open Access
• [Journal Article] Modulation of autoimmune pathogenesis by T cell-triggered inflammatory cell death. (2019)
  • Author(s): Sasaki, K., Himeno, A., Nakagawa, T., Sasaki, Y., Kiyonari, H. and Iwai, K.
  • Journal Title: Nature Communications Volume: 10 Issue: 1 Pages: 3878-3878
  • DOI: 10.1038/s41467-019-11858-7
  • NAID: 120006716601
  • Peer Reviewed / Open Access
• [Journal Article] Loss of NFAT2 expression results in the acceleration of clonal evolution in chronic lymphocytic leukemia (2018)
  • Author(s): Muller David J.、Wirths Stefan、Fuchs Alexander R.、Marklin Melanie、Heitmann Jonas S.、Sturm Marc、Haap Michael、Kirschniak Andreas、Sasaki Yoshiteru、Kanz Lothar、Kopp Hans-Georg、Muller Martin R.
  • Journal Title: Journal of Leukocyte Biology Volume: 105 Issue: 3 Pages: 531-538
  • DOI: 10.1002/jlb.2ab0218-076rr
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Crucial Role of Linear Ubiquitin Chain Assembly Complex-Mediated Inhibition of Programmed Cell Death in TLR4-Mediated B Cell Responses and B1b Cell Development (2018)
  • Author(s): Sasaki Yoshiteru、Iwai Kazuhiro
  • Journal Title: The Journal of Immunology Volume: 印刷中 Issue: 10 Pages: 3438-3449
  • DOI: 10.4049/jimmunol.1701526
  • Peer Reviewed