Regulation of ER-localized mannosidase EDEM2 via the intermolecular disulfide bond

• Project/Area Number: 18K06110
• 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: Kyoto University
• Principal Investigator: Okada Tetsuya 京都大学, 理学研究科, 助教 (70378529)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 小胞体 / マンノシダーゼ / タンパク分解 / 小胞体関連分解 / タンパク質分解 / 糖鎖

Outline of Final Research Achievements

Mannose trimming of N-glycan regulates endoplasmic reticulum (ER)-associated degradation of misfolded glycoproteins. In this study, we found that EDEM2, a putative ER-localized mannosidase, was stably disulfide-bounded to TXNDC11, an ER-localized protein with five thioredoxin-like domains. This covalent association was essential for mannose trimming and glycoprotein degradation. We also clearly demonstrated for the first time that EDEM2-TXNDC11 complex purified from culture cells had mannosidase activity against N-glycan in vitro.

Academic Significance and Societal Importance of the Research Achievements

本研究によるEDEM2-TXNDC11複合体のマンノシダーゼ活性検出により、遺伝子破壊解析の知見から我々が提唱していた小胞体のマンノース刈り込みの分子機構が生化学的にも立証された。小胞体における不要タンパク質の分解は、細胞の生命活動において不可欠な機構である。TXNDC11によるEDEM2の活性制御の発見とEDEMタンパク質の酵素活性の測定法の確立により、その分子機構の理解がより深まると期待される。

Research Products

• [Journal Article] EDEM2 stably disulfide-bonded to TXNDC11 catalyzes the first mannose trimming step in mammalian glycoprotein ERAD (2020)
  • Author(s): George Ginto、Ninagawa Satoshi、Yagi Hirokazu、Saito Taiki、Ishikawa Tokiro、Sakuma Tetsushi、Yamamoto Takashi、Imami Koshi、Ishihama Yasushi、Kato Koichi、Okada Tetsuya、Mori Kazutoshi
  • Journal Title: eLife Volume: 9
  • DOI: 10.7554/elife.53455
  • NAID: 120006817590
  • Peer Reviewed / Open Access
• [Journal Article] 特集 細胞高次機能をつかさどるオルガネラコミュニケーション Ⅰ.小胞体 小胞体に存在する複数のオルガネラ･ゾーン (2018)
  • Author(s): 森 和俊、岡田 徹也
  • Journal Title: 生体の科学 Volume: 69 Issue: 6 Pages: 527-531
  • DOI: 10.11477/mf.2425200913
  • ISSN: 0370-9531, 1883-5503
  • Year and Date: 2018-12-15
• [Presentation] A Role of a Thioredoxin Protein on EDEM2 Mannosidase Activity (2018)
  • Author(s): Ginto George, Satoshi Ninagawa, Tokiro Ishikawa, Tetsuya Okada, Kazutoshi Mori
  • Organizer: The 91st Annual Meeting of the Japanese Biochemical Society
• [Remarks] 京都大学大学院理学研究科 生物科学専攻 生物物理学教室 ゲノム情報分野
  • URL: http://www.upr.biophys.kyoto-u.ac.jp