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Physiological and pathological roles of GPI side chains and free GPI

Research Project

Project/Area Number 16H04753
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Structural biochemistry
Research InstitutionOsaka University

Principal Investigator

Kinoshita Taroh  大阪大学, 微生物病研究所, 寄附研究部門教授 (10153165)

Project Period (FY) 2016-04-01 – 2021-03-31
Project Status Completed (Fiscal Year 2020)
Budget Amount *help
¥17,160,000 (Direct Cost: ¥13,200,000、Indirect Cost: ¥3,960,000)
Fiscal Year 2020: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000)
Fiscal Year 2019: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000)
Fiscal Year 2018: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000)
Fiscal Year 2017: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000)
Fiscal Year 2016: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Keywords糖脂質 / 糖鎖
Outline of Final Research Achievements

Glycosylphosphatidylinositols (GPIs) are glycolipids that are attached to various proteins and act as their membrane anchors on the cell surface. GPIs also exist as free, non-protein linked glycolipids. The structure of core glycan part is conserved whereas side chains make variation. We aimed to clarify how GPI side chains are synthesized and to understand intracellular dynamics and pathological roles of free GPIs. We identified two enzymes that are involved in generation of a major side chain in mammalian GPI. Concerning free GPI, we found that GPIs synthesized in the endoplasmic reticulum of cells defective in GPI transamidase that transfers GPI to proteins, are transported to the cell surface. Using free GPI levels as a measure of GPI biosynthesis levels, we found a mechanism of GPI biosynthesis regulation. We also demonstrated that abnormally accumulated free GPIs cause autoinflammation.

Academic Significance and Societal Importance of the Research Achievements

ヒトが持つタンパク質の約160種には糖脂質であるGPI(グリコシルホスファチジルイノシトール)が結合しており、GPIによって細胞膜に係留されて機能している。GPIの生合成が異常になると先天性グリコシルホスファチジルイノシトール(GPI)欠損症や発作性夜間ヘモグロビン尿症と言った難病を発症する。GPIの糖鎖部分の骨格は共通構造をしているが、側鎖によって多様性が生まれる。しかし側鎖の生合成機構は未解明であった。また、GPIはタンパク質に結合しないフリーの糖脂質としても存在することが知られているが、その生理的意義や病理的意義は不明であった。本研究の成果はこれらの課題に一定の進展をもたらした。

Report

(6 results)
  • 2020 Annual Research Report   Final Research Report ( PDF )
  • 2019 Annual Research Report
  • 2018 Annual Research Report
  • 2017 Annual Research Report
  • 2016 Annual Research Report
  • Research Products

    (27 results)

All 2021 2020 2019 2018 2016 Other

All Int'l Joint Research (2 results) Journal Article (11 results) (of which Int'l Joint Research: 8 results,  Peer Reviewed: 11 results,  Open Access: 10 results) Presentation (13 results) (of which Int'l Joint Research: 7 results,  Invited: 11 results) Remarks (1 results)

  • [Int'l Joint Research] Radboud University Medical Center(オランダ)

    • Related Report
      2020 Annual Research Report
  • [Int'l Joint Research] King’s College Hospital(英国)

    • Related Report
      2020 Annual Research Report
  • [Journal Article] α2,3 linkage of sialic acid to a GPI anchor and an unpredicted GPI attachment site in human prion protein2020

    • Author(s)
      Kobayashi Atsushi、Hirata Tetsuya、Nishikaze Takashi、Ninomiya Akinori、Maki Yuta、Takada Yoko、Kitamoto Tetsuyuki、Kinoshita Taroh
    • Journal Title

      Journal of Biological Chemistry

      Volume: 295 Issue: 22 Pages: 7789-7798

    • DOI

      10.1074/jbc.ra120.013444

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] PGAP6, a GPI-specific phospholipase A2, has narrow substrate specificity against GPI-anchored proteins2020

    • Author(s)
      Lee Gun-Hee、Fujita Morihisa、Nakanishi Hideki、Miyata Haruhiko、Ikawa Masahito、Maeda Yusuke、Murakami Yoshiko、Kinoshita Taroh
    • Journal Title

      Journal of Biological Chemistry

      Volume: 295 Issue: 42 Pages: 14501-14509

    • DOI

      10.1074/jbc.ra120.014643

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Calnexin mediates the maturation of GPI-anchors through ER retention2020

    • Author(s)
      Guo Xin-Yu、Liu Yi-Shi、Gao Xiao-Dong、Kinoshita Taroh、Fujita Morihisa
    • Journal Title

      Journal of Biological Chemistry

      Volume: 295 Issue: 48 Pages: 16393-16410

    • DOI

      10.1074/jbc.ra120.015577

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Bi-allelic Variants in the GPI Transamidase Subunit PIGK Cause a Neurodevelopmental Syndrome with Hypotonia, Cerebellar Atrophy, and Epilepsy2020

    • Author(s)
      Nguyen Thi Tuyet Mai、Murakami Yoshiko、Mobilio Sabrina、Rosenfeld Jill A.、St-Denis Anik、Elrick Matthew J.、Anselm Irina、Rodan Lance H.、Tartaglia Marco、Gleeson Joseph、Kinoshita Taroh、Campeau Philippe M.
    • Journal Title

      The American Journal of Human Genetics

      Volume: 106 Issue: 4 Pages: 484-495

    • DOI

      10.1016/j.ajhg.2020.03.001

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Cross-talks of glycosylphosphatidylinositol biosynthesis with glycosphingolipid biosynthesis and ER-associated degradation2020

    • Author(s)
      Wang Yicheng、Maeda Yusuke、Liu Yi-Shi、Takada Yoko、Ninomiya Akinori、Hirata Tetsuya、Fujita Morihisa、Murakami Yoshiko、Kinoshita Taroh
    • Journal Title

      Nature Communications

      Volume: 11 Issue: 1 Pages: 860-860

    • DOI

      10.1038/s41467-020-14678-2

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Complement and inflammasome overactivation mediates paroxysmal nocturnal hemoglobinuria with autoinflammation.2019

    • Author(s)
      Hochsmann B, Murakami Y, Osato M, Knaus A, Kawamoto M, Inoue N, Hirata T, Murata S, Anliker M, Eggermann T, Jager M, Floettmann R, Hollein A, Murase S, Ueda Y, Nishimura JI, Kanakura Y, Kohara N, Schrezenmeier H, Krawitz PM, Kinoshita T.
    • Journal Title

      The Journal of Clinical Investigation

      Volume: 129 Issue: 12 Pages: 5123-5136

    • DOI

      10.1172/jci123501

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Mutations in PIGB Cause an Inherited GPI Biosynthesis Defect with an Axonal Neuropathy and Metabolic Abnormality in Severe Cases2019

    • Author(s)
      Murakami Yoshiko, et al., Matsumoto Naomichi, et al., Campeau Philippe M.
    • Journal Title

      The American Journal of Human Genetics

      Volume: 105 Issue: 2 Pages: 384-394

    • DOI

      10.1016/j.ajhg.2019.05.019

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Mutations in PIGU Impair the Function of the GPI Transamidase Complex, Causing Severe Intellectual Disability, Epilepsy, and Brain Anomalies2019

    • Author(s)
      Knaus Alexej、Kort?m Fanny、Kleefstra Tjitske、Stray-Pedersen Asbj?rg、?uki? Dejan、Murakami Yoshiko、Gerstner Thorsten、van Bokhoven Hans、Iqbal Zafar、Horn Denise、Kinoshita Taroh、Hempel Maja、Krawitz Peter M.
    • Journal Title

      The American Journal of Human Genetics

      Volume: 105 Issue: 2 Pages: 395-402

    • DOI

      10.1016/j.ajhg.2019.06.009

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Free, unlinked glycosylphosphatidylinositols on mammalian cell surfaces revisited2019

    • Author(s)
      Wang Yicheng、Hirata Tetsuya、Maeda Yusuke、Murakami Yoshiko、Fujita Morihisa、Kinoshita Taroh
    • Journal Title

      Journal of Biological Chemistry

      Volume: 294 Issue: 13 Pages: 5038-5049

    • DOI

      10.1074/jbc.ra119.007472

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Congenital Defects in the Expression of the Glycosylphosphatidylinositol-Anchored Complement Regulatory Proteins CD59 and Decay-Accelerating Factor2018

    • Author(s)
      Kinoshita Taroh
    • Journal Title

      Seminars in Hematology

      Volume: 55 Issue: 3 Pages: 136-140

    • DOI

      10.1053/j.seminhematol.2018.04.004

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Identification of a Golgi GPI-N-acetylgalactosamine transferase with tandem transmembrane regions in the catalytic domain2018

    • Author(s)
      Hirata Tetsuya、Mishra Sushil K.、Nakamura Shota、Saito Kazunobu、Motooka Daisuke、Takada Yoko、Kanzawa Noriyuki、Murakami Yoshiko、Maeda Yusuke、Fujita Morihisa、Yamaguchi Yoshiki、Kinoshita Taroh
    • Journal Title

      Nature Coomunications

      Volume: 9 Issue: 1 Pages: 405-405

    • DOI

      10.1038/s41467-017-02799-0

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] GPIアンカー欠損症の分子病態2021

    • Author(s)
      木下タロウ
    • Organizer
      名城大学難治疾患研究センターセミナー
    • Related Report
      2020 Annual Research Report
    • Invited
  • [Presentation] 小胞体におけるGPI生合成の制御2021

    • Author(s)
      木下タロウ
    • Organizer
      大阪大学タンパク研セミナー
    • Related Report
      2020 Annual Research Report
    • Invited
  • [Presentation] Molecular pathogenesis of GPI anchor deficiencies2020

    • Author(s)
      Taroh Kinoshita
    • Organizer
      Mexican Society of Human Genetics
    • Related Report
      2020 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Cross-talk of glycosylphosphatidylinositol biosynthesis with glycosphingolipid biosynthesis2020

    • Author(s)
      Taroh Kinoshita
    • Organizer
      Society for Glycobiology 2020 Virtual Annual Meeting
    • Related Report
      2020 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] 補体とGPIアンカーに出会って2020

    • Author(s)
      木下タロウ
    • Organizer
      第73回日本細菌学会関西支部会総会
    • Related Report
      2020 Annual Research Report
    • Invited
  • [Presentation] Glycosylphosphatidylinositol: glycan and phospholipid in one molecule2020

    • Author(s)
      Taroh Kinoshita
    • Organizer
      RIKEN International Symposium on Glyco-lipidologue
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Basic science and potential treatment of GPI disorders2020

    • Author(s)
      Taroh Kinoshita
    • Organizer
      SBP Medical Discovery Institute Rare Disease Day Symposium
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Side-chain modification of mammalian GPI-anchors2019

    • Author(s)
      Taroh Kinoshita
    • Organizer
      Gordon Research Conference on Carbohydrates
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Regulation of glycosylphosphatidylinositol biosynthesis2019

    • Author(s)
      Taroh Kinoshita
    • Organizer
      International Symposium on Glycoconjugates (Glyco 25)
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Quantity control of GPI biosynthesis2019

    • Author(s)
      Taroh Kinoshita
    • Organizer
      42nd Annual Meeting of The Molecular Biology Society of Japan
    • Related Report
      2019 Annual Research Report
    • Invited
  • [Presentation] Interactions between GPI-anchor biosynthesis and glycosphingolipid biosynthesis2019

    • Author(s)
      Taroh Kinoshita
    • Organizer
      Gordon Research Conference on Glycobiology
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Free glycosylphosphatidylinositols sre abnormally accumulated on the cell surface of GPI-transamidase-deficient mammalian cells2016

    • Author(s)
      王 宜成
    • Organizer
      第89回日本生化学会大会
    • Place of Presentation
      仙台市
    • Year and Date
      2016-09-26
    • Related Report
      2016 Annual Research Report
  • [Presentation] 立体構造モデルに基づいたGPI-GalNAc 転移酵素PGAP4によるGPI側鎖合成機構2016

    • Author(s)
      平田哲也
    • Organizer
      第35回日本糖質学会年会
    • Place of Presentation
      高知市
    • Year and Date
      2016-09-02
    • Related Report
      2016 Annual Research Report
  • [Remarks] 大阪大学微生物病研究所・籔本難病解明寄附研究部門

    • URL

      http://yabumoto.biken.osaka-u.ac.jp

    • Related Report
      2019 Annual Research Report 2018 Annual Research Report

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Published: 2016-04-21   Modified: 2022-01-27  

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