Regulation mechanism of Glycosphingolipids metabolism by O-GlcNACylation

• Project/Area Number: 18K06120
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 43030:Functional biochemistry-related
• Research Institution: Nagoya University (2021-2022); Kawasaki Medical School (2018-2020)
• Principal Investigator: Go Shinji 名古屋大学, 糖鎖生命コア研究所, 特任准教授 (10458218)
• Project Period (FY): 2018-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2021: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2020: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2019: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
• Keywords: 糖鎖 / 糖脂質 / シアル酸 / リソソーム / O-GlcNAc / スフィンゴ糖脂質 / O-GlcNAc修飾 / スフィンゴ脂質

Outline of Final Research Achievements

We have been analyzing the integrated regulatory mechanism of cellular glycosylation by "O-GlcNAcylation (addition of the sugar N-acetylglucosamine (GlcNAc) to serine/threonine residues of proteins)," a post-translational modification of intracellular (cytoplasmic and nuclear) proteins.
In this study, it was clarified for the first time that O-GlcNAcylation regulates the biosynthesis of glycolipids, the metabolism of sialic acid, a sugar important for glycans, and lysosomal functions involved in the catabolism (degradation) of glycans. These findings suggest that cells may use GlcNAc as a sensor to sense the status of cellular glycans and to control appropriate glycan metabolism in an integrated manner.

Academic Significance and Societal Importance of the Research Achievements

これまで、糖鎖の生合成、分解は個別に研究が進められてきた。今回、GlcNAcを中心として（特にO-GlcNAc化を介して）、細胞の糖鎖代謝が統合的に連動して制御されていることを見出した。
また、GlcNAcアナログを用いた、糖鎖発現制御に関しても道筋が得られており、創薬、研究ツール開発にもつながることが期待できる。

Research Products

• [Journal Article] The Urinary Bladder is Rich in Glycosphingolipids Composed of Phytoceramides (2022)
  • Author(s): Watanabe Takashi、Suzuki Akemi、Ohira Shin、Go Shinji、Ishizuka Yuta、Moriya Takuya、Miyaji Yoshiyuki、Nakatsuka Tota、Hirata Keita、Nagai Atsushi、Matsuda Junko
  • Journal Title: Journal of Lipid Research Volume: 63 Issue: 12 Pages: 100303-100303
  • DOI: 10.1016/j.jlr.2022.100303
  • Peer Reviewed / Open Access
• [Journal Article] Synthesis of O-Linked Glycoconjugates in the Nervous System (2022)
  • Author(s): Inokuchi Jin-Ichi、Go Shinji、Hirabayashi Yoshio
  • Journal Title: Adv Neurobiol . Volume: 29 Pages: 95-116
  • DOI: 10.1007/978-3-031-12390-0_4
  • ISBN: 9783031123894, 9783031123900
• [Journal Article] Involvement of acid ceramidase in the degradation of bioactive N-acylethanolamines (2021)
  • Author(s): Tsuboi Kazuhito、Tai Tatsuya、Yamashita Ryouhei、Ali Hanif、Watanabe Takashi、Uyama Toru、Okamoto Yoko、Kitakaze Keisuke、Takenouchi Yasuhiro、Go Shinji、Rahman Iffat Ara Sonia、Houchi Hitoshi、Tanaka Tamotsu、Okamoto Yasuo、Tokumura Akira、Matsuda Junko、Ueda Natsuo
  • Journal Title: Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids Volume: 1866 Issue: 9 Pages: 158972-158972
  • DOI: 10.1016/j.bbalip.2021.158972
  • Peer Reviewed / Open Access
• [Journal Article] Reduction in MIR-219 expression underlies cellular pathogenesis of oligodendrocytes in a mouse model of Krabbe disease. (2021)
  • Author(s): Inamura N, Go S, Watanabe T, Takase H, Takakura N, Nakayama A, Takebayashi H, Matsuda J, Enokido Y.
  • Journal Title: Brain Pathology Volume: － Issue: 5 Pages: 12951-12951
  • DOI: 10.1111/bpa.12951
  • Peer Reviewed / Open Access
• [Presentation] O-GlcNAc修飾を介したシアル酸代謝制御機構 (2018)
  • Author(s): 郷 慎司
  • Organizer: 日本生化学会