Defense mechanism against lifestyle diseases by ubiquitin-like modifier UFM1

• Project/Area Number: 16H06221
• Research Category: Grant-in-Aid for Young Scientists (A)
• Allocation Type: Single-year Grants
• Research Field: Environmental physiology(including physical medicine and nutritional physiology)
• Research Institution: Hokkaido University
• Principal Investigator: watanabe masashi 北海道大学, 医学研究院, 講師 (10632424)
• Project Period (FY): 2016-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥25,090,000 (Direct Cost: ¥19,300,000、Indirect Cost: ¥5,790,000); Fiscal Year 2019: ¥6,110,000 (Direct Cost: ¥4,700,000、Indirect Cost: ¥1,410,000); Fiscal Year 2018: ¥6,110,000 (Direct Cost: ¥4,700,000、Indirect Cost: ¥1,410,000); Fiscal Year 2017: ¥6,110,000 (Direct Cost: ¥4,700,000、Indirect Cost: ¥1,410,000); Fiscal Year 2016: ¥6,760,000 (Direct Cost: ¥5,200,000、Indirect Cost: ¥1,560,000)
• Keywords: ユビキチン様修飾分子 / UFM1 / Ufm1 / ゲノム / クロマチン

Outline of Final Research Achievements

UFM1ylated proteins containing substrates reported previously were identified by mass spectrometric analysis of affinity-purified UFM1-conjugates. We confirmed that some of these substrate candidates were actually subjected to UFM1 conjugation by in vivo UFMylation assay. Among these substrates, we focused on LTA4H, which was one of leukotriene-metabolizing enzyme. We found that UFM1 not only covalently binds to LTA4H, but also non-covalently. Furthermore, we found that UFM1 knockdown increased the amount of leukotriene B4, which was the metabolite of LTA4H. These results suggest that UFM1 regulates leukotriene metabolism via LTA4H.

Academic Significance and Societal Importance of the Research Achievements

現代の社会において、日本人の死亡原因に生活習慣病が多くを占めるようになり、この中でも動脈硬化の進行をいかに制御するかということが焦点となっている。厚生労働省の平成２２年度国民医療費の調査によると、生活習慣病は約３割を占めており、社会・倫理的な観点からも重要である。UFM1は生活習慣病に対して防御的に機能することが知られているが、その詳しいメカニズムはこれまでのところ明らかではなかった。本研究により、生活習慣病との関連が指摘されている慢性炎症の制御因子として重要なロイコトリエン代謝酵素とUFM1の関係が明らかとなってきた。治療標的として将来の医学の発展への貢献も期待できると思われる。

Research Products

• [Journal Article] The role of Mediator and Little Elongation Complex in transcription termination (2020)
  • Author(s): Takahashi H, Ranjan A, Chen S, Suzuki H, Shibata M, Hirose T, Hirose H, Sasaki K, Abe R, Chen K, He Y, Zhang Y, Takigawa I, Tsukiyama T, Watanabe M, Fujii S, Iida M, Yamamoto J, Yamaguchi Y, Suzuki Y, Matsumoto M, Nakayama KI, Washburn P, Saraf A, Florens L, Sato S, Tomomori-Sato C, Conaway RC, Conaway JW, Hatakeyama S
  • Journal Title: Nature Communications Volume: 11 Issue: 1 Pages: 1-20
  • DOI: 10.1038/s41467-020-14849-1
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Brain-Derived Neurotrophic Factor Improves Limited Exercise Capacity in Mice With Heart Failure (2018)
  • Author(s): Matsumoto Junichi、et al. Hatakeyama Shigetsugu、Matsumoto Masaki、Nakayama Keiichi I.、Otsuka Yutaro、Sabe Hisataka、Tsutsui Hiroyuki、Anzai Toshihisa
  • Journal Title: Circulation Volume: 138 Issue: 18 Pages: 2064-2066
  • DOI: 10.1161/circulationaha.118.035212
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Loss of TRIM29 Alters Keratin Distribution to Promote Cell Invasion in Squamous Cell Carcinoma. (2018)
  • Author(s): Yanagi T, Watanabe M, Hata H, Kitamura S, Imafuku K, Yanagi H, Homma A, Wang L, Takahashi H, Shimizu H, Hatakeyama S.
  • Journal Title: Cancer Res Volume: 78 Issue: 24 Pages: 6795-6806
  • DOI: 10.1158/0008-5472.can-18-1495
  • Peer Reviewed
• [Journal Article] Mutations in bassoon in individuals with familial and sporadic progressive supranuclear palsy-like syndrome (2018)
  • Author(s): Yabe I, Yaguchi H, Kato Y, Miki Y, Takahashi H, Tanikawa S, Shirai S, Takahashi I, Kimura M, Hama Y, Matsushima M, Fujioka S, Kano T, Watanabe M, Nakagawa S, Kunieda Y, Ikeda Y, Hasegawa M, Nishihara H, Ohtsuka T, Tanaka S, Tsuboi Y, Hatakeyama S, Wakabayashi K, Sasaki H
  • Journal Title: Sci Rep Volume: 8 Issue: 1 Pages: 819-819
  • DOI: 10.1038/s41598-018-19198-0
  • NAID: 120006377499
  • Peer Reviewed / Open Access
• [Journal Article] Anti-Sez6l2 antibody, detected in a patient with immune-mediated cerebellar ataxia, inhibits complex formation of GluR1 and Sez6l2 (2018)
  • Author(s): Yaguchi, H., Yabe, I., Takahashi, H., Watanabe, M., Nomura, T., Kano, T., Watanabe, M. and Hatakeyama, S.
  • Journal Title: J. Neurol. Volume: 265 Issue: 4 Pages: 962-965
  • DOI: 10.1007/s00415-018-8785-z
  • Peer Reviewed
• [Journal Article] Sez6l2 regulates phosphorylation of ADD and neuritogenesis (2017)
  • Author(s): Yaguchi, H., Yabe, I., Takahashi, H., Watanabe, M., Nomura, T., Kano, T., Matsumoto, M., Nakayama, K.I., Watanabe, M. and Hatakeyama, S.
  • Journal Title: Biochem. Biophys. Res. Commun. Volume: 494 Issue: 1-2 Pages: 234-241
  • DOI: 10.1016/j.bbrc.2017.10.047
  • Peer Reviewed
• [Journal Article] Fine-tuning of thymocyte development by ubiquitination-mediated stability control of the ESCRT protein CHMP5 (2017)
  • Author(s): Watanabe, M. and Hatakeyama, S.
  • Journal Title: Cell. Moll. Immnol. Volume: 14 Issue: 12 Pages: 957-959
  • DOI: 10.1038/cmi.2017.91
  • Peer Reviewed
• [Journal Article] TRIM proteins and diseases. (2017)
  • Author(s): Watanabe, M. and Hatakeyama, S
  • Journal Title: J. Biochem. Volume: 161 Pages: 135-144
  • DOI: 10.1093/jb/mvw087
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] The novel heart-specific RING finger protein 207 is involved in energy metabolism in cardiomyocytes. (2016)
  • Author(s): Mizushima, W., Takahashi , H., Watanabe, M., Kinugawa, S., Matsushima, S., Takada, S., Yokota, T., Furihata, T., Matsumoto, J., Tsuda, M., Chiba, I., Nagashima, S., Yanagi, S., Matsumoto, M., Nakayama, K.I., Tsutsui, H. and Hatakeyama, S.
  • Journal Title: J. Mol. Cell. Cardiol. Volume: 100 Pages: 43-53
  • DOI: 10.1016/j.yjmcc.2016.09.013
  • NAID: 120006360069
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] p53 represses the transcription of snRNA genes by preventing the formation of little elongation complex (2016)
  • Author(s): Anwar, D., Takahashia, H., Watanabe, M., Suzuki, M., Fukuda, S., Hatakeyama, S.
  • Journal Title: Biochim. Biophys. Acta-Gene Regul. Mech. Volume: 1859 Issue: 8 Pages: 975-982
  • DOI: 10.1016/j.bbagrm.2016.06.001
  • NAID: 120006328999
  • Peer Reviewed / Acknowledgement Compliant
• [Presentation] 自然免疫シグナルに関わるユビキチンリガーゼ群の網羅的な基質同定と解析 (2019)
  • Author(s): 渡部 昌
  • Organizer: 第92回日本生化学会大会
  • Invited
• [Presentation] Comprehensive identification of E3 ubiquitin ligase substrates by fusion of TUBE and ligase trapping methods. (2018)
  • Author(s): Watanabe M
  • Organizer: The 2nd GI-CoRE GSQ, GSB, & IGM JOINT SYMPOSIUM Quantum, Informatics, Biology & Medicine
  • Int'l Joint Research / Invited
• [Presentation] Identification of E3 ligase substrates by fusion of TR-TUBE and ligase trap methods. (2017)
  • Author(s): Watanabe M
  • Organizer: Cold Spring Harbor Laboratory Meeting on the Ubiquitin Family
  • Int'l Joint Research
• [Presentation] The E3 ubiquitin ligase TRIM23 regulates adipocyte differentiation via stabilization of the adipogenic activator PPARγ (2016)
  • Author(s): 渡部 昌, 高橋秀尚, 畠山鎮次
  • Organizer: 第39回日本分子生物学会年会
  • Place of Presentation: パシフィコ横浜（神奈川県・横浜市）
  • Year and Date: 2016-12-01
  • Invited
• [Presentation] ユビキチンリガーゼTRIM23は非定型ポリユビキチン化によるPPARγの安定化を介して脂肪細胞分化を制御する (2016)
  • Author(s): 渡部 昌, 高橋秀尚, 畠山鎮次
  • Organizer: 第89回日本生化学会大会
  • Place of Presentation: 東北大学川内北キャンパス （宮城県・仙台市）
  • Year and Date: 2016-09-27
• [Presentation] ユビキチンE3リガーゼTRIM23は非定型ポリユビキチン化によるPPARγの安定化を介して脂肪細胞分化を制御する (2016)
  • Author(s): 渡部 昌, 高橋秀尚, 畠山鎮次
  • Organizer: 第68回日本細胞生物学会大会
  • Place of Presentation: 京都テルサ（京都府・京都市）
  • Year and Date: 2016-06-15
• [Presentation] ユビキチンリガーゼTRIM23はPPARγの安定化を介して脂肪細胞分化を制御する (2016)
  • Author(s): 渡部 昌, 高橋秀尚, 畠山鎮次
  • Organizer: 第89回日本内分泌学会学術総会
  • Place of Presentation: 国立京都国際会館（京都府・京都市）
  • Year and Date: 2016-04-21
• [Book] Advances in Medicine and Biology. Volume 120 (2017)
  • Author(s): Masashi Watanabe and Shigetsugu Hatakeyama
  • Total Pages: 23
  • Publisher: Nova Science Publishers