Regulatory mechanisms of activated B cell fate which contribute diversity of immune response

• Project/Area Number: 16H05138
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: General medical chemistry
• Research Institution: University of Fukui
• Principal Investigator: Sugai Manabu 福井大学, 学術研究院医学系部門, 教授 (90303891)
• Co-Investigator(Kenkyū-buntansha): 黒岡 尚徳 相模女子大学, 栄養科学部, 教授 (00293879) ; 林 達成 福井大学, 学術研究院医学系部門, 特命助教 (80781111) ; 南部 由希子 福井大学, 学術研究院医学系部門, 准教授 (70580380) ; 森 健太郎 福井大学, 学術研究院医学系部門, 助教 (50397296)
• Research Collaborator: SAKAMOTO hiroshi
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥17,420,000 (Direct Cost: ¥13,400,000、Indirect Cost: ¥4,020,000); Fiscal Year 2018: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000); Fiscal Year 2017: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000); Fiscal Year 2016: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000)
• Keywords: B cell / Mitochondria / Metabolism / Differentiation / クラススイッチ組換え / 形質細胞分化 / ミトコンドリア / クラススイッチ組み換え / B細胞 / 代謝 / 分化 / 慢性炎症 / 自己免疫疾患 / 腫瘍免疫

Outline of Final Research Achievements

The acquired immune response is mediated by lymphocytes, which express highly diverse receptors. After lymphocytes specifically recognize the antigen　through their specific receptors, immune reactions started. Among the acquired immune cells, B lymphocytes, which produce immunoglobulin, differentiate into various cells upon activation. Precise mechanism that govern cell fate determination processes of activated B cells are not well understood. We previously found that mitochondrial status influence cell fate determination of activated B cells. For instance, the choice of PCD (plasma cell differentiation) or CSR (class switch recombination), which occurs in activated B cells, was dependent on mitochondrial functional activity. In this study, we examined in more detail the control mechanism of activated B cell differentiation by the difference in mitochondrial function.

Academic Significance and Societal Importance of the Research Achievements

細胞分化を司る転写因子ネットワークの重要性は既に広く知られているが、分化決定の初期過程や、その後引き続いて確立される安定した転写因子ネットワーク（分化決定）に至る過程、さらには安定した分化状態から別の分化状態に移行する過程の詳細は不明である。本研究では、この未解明な分野に光を当て、その一端を明らかにした事によって、細胞分化の理解に貢献すると考える。

Research Products

• [Journal Article] Dephosphorylation of protamine 2 at serine 56 is crucial for murine sperm maturation in vivo (2019)
  • Author(s): Itoh Katsuhiko、Kondoh Gen、Miyachi Hitoshi、Sugai Manabu、Kaneko Yoshiyuki、Kitano Satsuki、Watanabe Hitomi、Maeda Ryota、Imura Akihiro、Liu Yu、Ito Chizuru、Itohara Shigeyoshi、Toshimori Kiyotaka、Fujita Jun
  • Journal Title: Science Signaling Volume: 12 Issue: 574 Pages: 7232-7234
  • DOI: 10.1126/scisignal.aao7232
  • Peer Reviewed / Open Access
• [Journal Article] Blocking LC3 lipidation and ATG12 conjugation reactions by ATG7 mutant protein containing C572S (2019)
  • Author(s): Nitta A, Hori K, Tanida I, Igarashi A, Deyama Y, Ueno T, Kominami E, Sugai M, Aoki K.
  • Journal Title: Biochem Biophys Res Commun. Volume: 508(2) Issue: 2 Pages: 521-526
  • DOI: 10.1016/j.bbrc.2018.11.158
  • Peer Reviewed
• [Journal Article] Immune responses against Lewis Y tumor-associated carbohydrate antigen displayed densely on self-assembling nanocarriers (2018)
  • Author(s): Yamazaki Yuji、Nambu Yukiko、Ohmae Masashi、Sugai Manabu、Kimura Shunsaku
  • Journal Title: Organic & Biomolecular Chemistry Volume: 16 Issue: 43 Pages: 8095-8105
  • DOI: 10.1039/c8ob01955j
  • Peer Reviewed
• [Journal Article] Direct evidence for the age-dependent demise of GNAS -mutated cells in oral fibrous dysplasia (2018)
  • Author(s): Isobe Yu、Takahashi Katsu、Kiso Honoka、Nakao Kazumasa、Ikeno Masayuki、Koyama Noriaki、Sugai Manabu、Shimizu Akira、Haga Hironori、Bessho Kazuhisa
  • Journal Title: Archives of Oral Biology Volume: 93 Pages: 133-140
  • DOI: 10.1016/j.archoralbio.2018.05.018
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Loss of Stemness, EMT, and Supernumerary Tooth Formation in Cebpb-/-Runx2+/- Murine Incisors. (2018)
  • Author(s): Saito K, Takahashi K, Huang B, Asahara M, Kiso H, Togo Y, Tsukamoto H, Mishima S, Nagata M, Iida M, Tokita Y, Asai M, Shimizu A, Komori T, Harada H, MacDougall M, Sugai M, Bessho K.
  • Journal Title: Scientific Reports Volume: 8 Issue: 1 Pages: 5169-5169
  • DOI: 10.1038/s41598-018-23515-y
  • NAID: 120006545187
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Publication Preview Source Id2 Determines Intestinal Identity through Repression of the Foregut Transcription Factor Irx5 (2018)
  • Author(s): Mori, K, Nakamura, H, Kurooka, H, Miyachi, H, Tamada, K, Sugai, M,Takumi, T, Yokota, Y
  • Journal Title: Mol Cell Biol Volume: 38 Issue: 9
  • DOI: 10.1128/mcb.00250-17
  • Peer Reviewed / Open Access
• [Journal Article] Inflammatory responses induce an identity crisis of alveolar macrophages, leading to pulmonary alveolar proteinosis. (2017)
  • Author(s): Ebina-Shibuya R, Matsumoto M, Kuwahara M, Jang KJ, Sugai M, Ito Y, Funayama R, Nakayama K, Sato Y, Ishii N, Okamura Y, Kinoshita K, Kometani K, Kurosaki T, Muto A, Ichinose M, Yamashita M, Igarashi K.
  • Journal Title: The Journal of biological chemistry Volume: 292 Issue: 44 Pages: 18098-18112
  • DOI: 10.1074/jbc.m117.808535
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Tubulointerstitial Nephritis with IgM-Positive Plasma Cells. (2017)
  • Author(s): Takahashi N, Kimura H et al
  • Journal Title: J Am Soc Nephrol. Volume: 28 Issue: 12 Pages: 3688-3698
  • DOI: 10.1681/asn.2016101074
  • Peer Reviewed / Open Access
• [Presentation] Mitochondrial function in cell fate determination of activated B cells (2017)
  • Author(s): Manabu Sugai
  • Organizer: Consortium of Biological Sciences 2017