Functional analysis of LUBAC in the inhibition of cell death and the activation in B cells.

• Project/Area Number: 26460573
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Immunology
• Research Institution: Kyoto University
• Principal Investigator: Sasaki Yoshiteru 京都大学, 医学研究科, 准教授 (80323004)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2014: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 免疫学 / ユビキチン / 細胞死 / B細胞 / シグナル伝達 / 免疫シグナル伝達 / Caspase / ERK

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. In this study I analyzed the role of LUBAC in TLR4-mediated cell death of B cells lacking LUBAC activity. I found that among two signal transduces downstream of TLR4, MyD88 and TRIF TRIF is responsible for this cell death because ablation of TRIF prevented TLR4-induced cell death of HOIP deficient B cells. I also discovered that deletion of RIP3, a critical regulator of necroptosis alone did not inhibit TLR4-induced cell death but the inhibition of Caspase-8 together with RIP3 deletion restored LPS-induced survival and cell proliferation of HOIP deficient B cells. These data show that LUBAC plays critical roles in the inhibition of Caspase-mediated apoptosis induced by TLR4 stimulation.

Research Products

• [Journal Article] Survival of mature T cells depends on signaling through HOIP. (2016)
  • Author(s): Okamura, K., Kitamura, A., Sasaki, Y., Chung, D.H., Kagami, S., Iwai, K., and Yasutomo, K.
  • Journal Title: Sci. Rep. Volume: 6 Issue: 1 Pages: 36135-36135
  • DOI: 10.1038/srep36135
  • NAID: 120005867034
  • Peer Reviewed / Open Access
• [Journal Article] Differential involvement of the NZF domains of SHARPIN and HOIL-1L in LUBAC-mediated cell death protection. (2016)
  • Author(s): Shimizu S, Fujita H, Sasaki Y, Tsuruyama T, Fukuda K, Iwai K.
  • Journal Title: Mol Cell Biol. Volume: 01049-15 Issue: 10 Pages: 1569-1583
  • DOI: 10.1128/mcb.01049-15
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Roles of the NF-κB pathway in B-lymphocyte biology. (2016)
  • Author(s): Sasaki, Y. and Iwai, K.
  • Journal Title: Current Topics in Microbiology and Immunology: B cell Receptor Signaling Volume: 393 Pages: 177-209
  • DOI: 10.1007/82_2015_479
  • ISBN: 9783319261317, 9783319261331
• [Journal Article] CRTAM determines the CD4+ cytotoxic T lymphocyte lineage. (2016)
  • Author(s): Takeuchi, A., Badr Mel, S., Miyauchi, K., Ishihara, C., Onishi, R., Guo, Z., Sasaki. Y., Ike, H., Takumi, A., Tsuji, NM., Murakami, Y., Katakai, T., Kubo, M. and Saito, T.
  • Journal Title: J. Exp. Med. Volume: 213 Issue: 1 Pages: 123-138
  • DOI: 10.1084/jem.20150519
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Gab1 and Mapk Signaling Are Essential in the Hair Cycle and Hair Follicle Stem Cell Quiescence. (2015)
  • Author(s): Akilli Ozturk, O, Pakula, H., Chmielowiec, J., Qi, J., Stein, S., Lan, L., Sasaki, Y., Rajewsky, K. and Birchmeier, W.
  • Journal Title: Cell Reports Volume: 13 Issue: 3 Pages: 561-572
  • DOI: 10.1016/j.celrep.2015.09.015
  • NAID: 120005829369
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A Key Oncogenic Role for Alternative NF-κB Signaling in DLBCL, Revealed Upon Interference With Terminal B cell Differentiation. (2015)
  • Author(s): Zhang, B., Calado, DP., Wang, Z., Frohler, S., Kochert, K., Qian, Y., Koralov, S., Schmidt-Supprian, M., Sasaki, Y., Unitt, C., Rodig, S., Chen, W., Dalla-Favera, R., Alt, FW., Pasqualucci, L. and Rajewsky, K.
  • Journal Title: Cell Reports Volume: 11 Pages: 715-726
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Immunoblot Analysis of Linear Polyubiquitination of NEMO. (2015)
  • Author(s): Sasaki, Y., Fujita, H., Nakai, M., and Iwai, K.
  • Journal Title: Methods in Molecular Biology, NF-kappaB Methods and Protocols Volume: 1280 Pages: 297-309
  • DOI: 10.1007/978-1-4939-2422-6_17
  • ISBN: 9781493924219, 9781493924226
  • Acknowledgement Compliant
• [Journal Article] Gliotoxin Suppresses NF-kappaB Activation by Selectively Inhibiting Linear Ubiquitin Chain Assembly Complex (LUBAC) (2015)
  • Author(s): Hiroki Sakamoto, Shinichiro Egashira, Nae Saito, Takayoshi Kirisako, Simon Miller, Yoshiteru Sasaki, Tadahiko Matsumoto, Manabu Shimonishi, Toru Komatsu, Takuya Terai, Tasuku Ueno, Kenjiro Hanaoka, Hirotatsu Kojima, Takayoshi Okabe, Soichi Wakatsuki, Kazuhiro Iwai, Tetsuo Nagano
  • Journal Title: ACS Chemical Biology Volume: 10 Issue: 3 Pages: 675-681
  • DOI: 10.1021/cb500653y
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Linear ubiquitin chains: NF-κB signalling, cell death, and beyond. (2014)
  • Author(s): Iwai, K., Fujita, H., and Sasaki, Y.
  • Journal Title: Nature Rev. Mol. Cell Biol. Volume: 15 Issue: 8 Pages: 503-508
  • DOI: 10.1038/nrm3836
  • Peer Reviewed
• [Journal Article] IFN-γ or IFN-α ameliorates chronic proliferative dermatitis by inducing expression of linear ubiquitin chain assembly complex. (2014)
  • Author(s): Tamiya H, Terao M, Takiuchi T, Nakahara M, Sasaki Y, Katayama I, Yoshikawa H, and Iwai K.
  • Journal Title: J. Immunol. Volume: 192 Issue: 8 Pages: 3793-3804
  • DOI: 10.4049/jimmunol.1302308
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Mechanism underlying IKK activation mediated by the linear ubiquitin chain assembly complex (LUBAC). (2014)
  • Author(s): Fujita, H., Rahighi, S., Akita, M., Kato, R., Sasaki, Y., Wakatsuki, S., and Iwai, K.
  • Journal Title: Mol. Cell. Biol. Volume: 34 Issue: 7 Pages: 1322-1335
  • DOI: 10.1128/mcb.01538-13
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] Linear polyubiquitination chains controls TRIF-dependent cell death in B cells induced by TLR4 stimulation. (2016)
  • Author(s): 佐々木義輝、岩井一宏
  • Organizer: 第８９回日本生化学会大会
  • Place of Presentation: 仙台国際センター
  • Year and Date: 2016-09-25
• [Presentation] LUBAC controls TLR4- and TRIF-mediated cell death in B cells (2015)
  • Author(s): 佐々木義輝
  • Organizer: 第４４回 日本免疫学会総会・学術集会
  • Place of Presentation: 札幌コンベンションセンター
  • Year and Date: 2015-11-18
• [Presentation] Necroptosis-mediated expression of ILC2 cells in cpm mice. (2014)
  • Author(s): 佐々木義輝、佐々木克博
  • Organizer: 第４３回日本免疫学会総会・学術集会
  • Place of Presentation: 国立京都国際会館
  • Year and Date: 2014-12-10 – 2014-12-12
• [Presentation] Toll様受容体(TLR)刺激によるBリンパ球活性化における直鎖状ポリユビキチン鎖の役割 (2014)
  • Author(s): 佐々木義輝、岩井一宏
  • Organizer: 第８７回日本生化学会大会
  • Place of Presentation: 国立京都国際会館
  • Year and Date: 2014-10-15 – 2014-10-18
  • Invited
• [Remarks]
  • URL: http://www.mcp.med.kyoto-u.ac.jp