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S-アシル化修飾ゾーンによるシナプス機能制御

Publicly Offered Research

Project AreaToward an integrative understanding of functional zones in organelles
Project/Area Number 20H04915
Research Category

Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)

Allocation TypeSingle-year Grants
Review Section Biological Sciences
Research InstitutionNational Institute for Physiological Sciences

Principal Investigator

深田 正紀  生理学研究所, 分子細胞生理研究領域, 教授 (00335027)

Project Period (FY) 2020-04-01 – 2022-03-31
Project Status Completed (Fiscal Year 2021)
Budget Amount *help
¥7,150,000 (Direct Cost: ¥5,500,000、Indirect Cost: ¥1,650,000)
Fiscal Year 2021: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000)
Fiscal Year 2020: ¥3,510,000 (Direct Cost: ¥2,700,000、Indirect Cost: ¥810,000)
KeywordsS-アシル化修飾 / タンパク質 / 脂質 / 酵素 / シナプス / PSD-95 / ADAM22 / ZDHHCタンパク質 / ABHD17 / ZDHHC
Outline of Research at the Start

S-アシル化脂質修飾は、ウイルスから動物、植物まで保存された普遍的なタンパク質の修飾反応である。S-アシル化は、タンパク質に飽和脂肪酸であるパルミチン酸を可逆的に付加することでタンパク質の細胞内での輸送や局在、機能を制御する。本研究で私共は、“細胞内局所で、S-アシル化酵素と脱S-アシル化酵素が協調して形成する「S-アシル化修飾ゾーン」が、タンパク質の特異的かつ動的な局在制御を担う”という仮説を検証する。

Outline of Annual Research Achievements

本研究では、神経細胞の高度に特殊化した細胞膜領域であるシナプス膜領域をモデルとして、その形成と機能発現における「S-アシル化修飾ゾーン」の役割に着目してきた。とりわけ、シナプス後部膜に濃縮する代表的な足場タンパク質“PSD-95”の集積機構について解析を進めてきた。最近、私共は、PSD-95がシナプス後部膜に濃縮するには、(1) S-アシル化修飾に加えて、(2) PSD-95結合タンパク質として見出していたADAM22との結合が重要であることを見出した(Fukata et al. PNAS 2021)。2021年度は、米国UCSFのNicoll博士との共同研究にて、ADAM22-PSD-95経路が海馬の長期増強(LTP, long term potentiation)と呼ばれるシナプス可塑性に関与しているかを検討した。その結果、ADAM22-PSD-95経路は、SAP102経路と協調して、LTP誘導に必須の役割を果たしていることを明らかにした(Chen X, Fukata et al. PNAS 2021)。さらに、私共はADAM22の輸送ゾーン(生合成経路と分解経路)について解析を進め、ADAM22はPKAによりリン酸化され、14-3-3タンパク質と強固に結合することで安定にシナプス膜に発現することを見出した。一方、このリン酸化を受けない遺伝子改変マウスを作製したところ、ADAM22は14-3-3と結合できずに分解されてしまい、脳内のADAM22の量が約40%にまで減少することを見出した(Yokoi et al. Cell Rep 2021)。以上の結果より、シナプス後部へのPSD-95の集積およびそのシナプス機能には、S-アシル化と共に膜タンパク質ADAM22との結合が重要であることが明らかになった。

Research Progress Status

令和3年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

令和3年度が最終年度であるため、記入しない。

Report

(2 results)
  • 2021 Annual Research Report
  • 2020 Annual Research Report
  • Research Products

    (32 results)

All 2022 2021 2020 Other

All Int'l Joint Research (11 results) Journal Article (12 results) (of which Int'l Joint Research: 10 results,  Peer Reviewed: 10 results,  Open Access: 9 results) Presentation (3 results) (of which Int'l Joint Research: 1 results,  Invited: 3 results) Book (1 results) Remarks (5 results)

  • [Int'l Joint Research] UCSF(米国)

    • Related Report
      2021 Annual Research Report
  • [Int'l Joint Research] UCL/The University of Edinburgh(英国)

    • Related Report
      2021 Annual Research Report
  • [Int'l Joint Research] University of Helsinki(フィンランド)

    • Related Report
      2021 Annual Research Report
  • [Int'l Joint Research] DZNE/Charite-Universitatsmedizin(ドイツ)

    • Related Report
      2021 Annual Research Report
  • [Int'l Joint Research] Aarhus University(デンマーク)

    • Related Report
      2021 Annual Research Report
  • [Int'l Joint Research]

    • Related Report
      2021 Annual Research Report
  • [Int'l Joint Research] UCSF/UCSD(米国)

    • Related Report
      2020 Annual Research Report
  • [Int'l Joint Research] DZNE(ドイツ)

    • Related Report
      2020 Annual Research Report
  • [Int'l Joint Research] IST(オーストラリア)

    • Related Report
      2020 Annual Research Report
  • [Int'l Joint Research] UCL/The University of Edinburgh(英国)

    • Related Report
      2020 Annual Research Report
  • [Int'l Joint Research] University of Helsinki(フィンランド)

    • Related Report
      2020 Annual Research Report
  • [Journal Article] Biallelic ADAM22 pathogenic variants cause progressive encephalopathy and infantile-onset refractory epilepsy2022

    • Author(s)
      van der Knoop M Marieke M*、Maroofian Reza*、Fukata Yuko*、van Ierland Yvette、Karimiani G Ehsan、Lehesjoki Anna-Elina、Muona Mikko、Paetau Anders、Miyazaki Yuri、Hirano Yoko、Selim Laila、-----32名-----、Striano Pasquale、Severino Mariasavina、Fukata Masaki#、Hilhorst-Hofstee Yvonne#、Houlden Henry#
    • Journal Title

      Brain

      Volume: - Issue: 7 Pages: 2301-2312

    • DOI

      10.1093/brain/awac116

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Trans-synaptic LGI1-ADAM22?MAGUK in AMPA and NMDA receptor regulation2021

    • Author(s)
      Fukata Yuko、Hirano Yoko、Miyazaki Yuri、Yokoi Norihiko、Fukata Masaki
    • Journal Title

      Neuropharmacology

      Volume: 194 Pages: 108628-108628

    • DOI

      10.1016/j.neuropharm.2021.108628

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] 14-3-3 proteins stabilize LGI1-ADAM22 levels to regulate seizure thresholds in mice2021

    • Author(s)
      Norihiko Yokoi, Yuko Fukata, Kei Okatsu, Atsushi Yamagata, Yan Liu , Makoto Sanbo, Yuri Miyazaki, Teppei Goto, Manabu Abe , Hidetoshi Kassai, Kenji Sakimura, Dies Meijer, Masumi Hirabayashi, Shuya Fukai, Masaki Fukata
    • Journal Title

      Cell Reports

      Volume: 37 Issue: 11 Pages: 110107-110107

    • DOI

      10.1016/j.celrep.2021.110107

    • NAID

      120007177780

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] A novel red fluorescence dopamine biosensor selectively detects dopamine in the presence of norepinephrine in vitro2021

    • Author(s)
      Nakamoto Chihiro、Goto Yuhei、Tomizawa Yoko、Fukata Yuko、Fukata Masaki、Harpsoe Kasper、Gloriam David E.、Aoki Kazuhiro、Takeuchi Tomonori
    • Journal Title

      Molecular Brain

      Volume: 14 Issue: 1 Pages: 173-173

    • DOI

      10.1186/s13041-021-00882-8

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Encephalitis patient-derived monoclonal GABAA receptor antibodies cause epileptic seizures2021

    • Author(s)
      Kreye Jakob、Wright K Sukhvir、van Casteren Adriana、Stoffler Laura、Machule Marie-Luise、Reincke S Momsen、Nikolaus Marc、van Hoof Scott、Sanchez-Sendin Elisa、Homeyer A Marie、Cordero Gomez Cesar、Kornau Hans-Christian、-----12名-----、Wickel Jonathan、Geis Christian、Fukata Yuko、Fukata Masaki、Pruss Harald
    • Journal Title

      Journal of Experimental Medicine

      Volume: 218

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] MAGUKs are essential, but redundant, in long-term potentiation2021

    • Author(s)
      Chen Xiumin、Fukata Yuko、Fukata Masaki、Nicoll Roger A.
    • Journal Title

      Proceedings of the National Academy of Sciences

      Volume: 118 Issue: 28

    • DOI

      10.1073/pnas.2107585118

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] LGI1-ADAM22-MAGUK configures transsynaptic nanoalignment for synaptic transmission and epilepsy prevention2021

    • Author(s)
      Fukata Yuko、Chen Xiumin、Chiken Satomi、Hirano Yoko、Yamagata Atsushi、Inahashi Hiroki、Sanbo Makoto、Sano Hiromi、Goto Teppei、Hirabayashi Masumi、Kornau Hans-Christian、Pruss Harald、Nambu Atsushi、Fukai Shuya、Nicoll Roger A.、Fukata Masaki
    • Journal Title

      Proceedings of the National Academy of Sciences

      Volume: 118 Issue: 3 Pages: 1-12

    • DOI

      10.1073/pnas.2022580118

    • NAID

      120006976050

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Canonical versus non-canonical transsynaptic signaling of neuroligin 3 tunes development of sociality in mice2021

    • Author(s)
      Yoshida T, Yamagata A, Imai A, Kim J, Izumi H, Nakashima S, Shiroshima T, Maeda A, Iwasawa-Okamoto S, Azechi K, Osaka F, Saitoh T, Maenaka K, Shimada T, Fukata Y, Fukata M, Matsumoto J, Nishijo H, Takao K, Tanaka S, Okabe S, Tabuchi K, Uemura T, Mishina M, Mori H & Fukai S
    • Journal Title

      Nature Communications

      Volume: 12(1) Issue: 1 Pages: 1848-1848

    • DOI

      10.1038/s41467-021-22059-6

    • NAID

      120006996978

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Encephalitis patient derived monoclonal GABAA receptor antibodies cause catatonia and epileptic seizures2021

    • Author(s)
      Kreye Jakob、Wright Sukhvir K.、van Casteren Adriana、Machule Marie-Luise、Reincke S. Momsen、Nikolaus Marc、Stoffler Laura、van Hoof Scott、Sanchez-Sendin Elisa、Kornau Hans-Christian、Kaindl Angela M.、Wilson Max A.、Greenhill Stuart、他5名、Geis Christian、Fukata Yuko、Fukata Masaki、Pruss Harald
    • Journal Title

      bioRxiv

      Volume: -

    • DOI

      10.1101/2021.01.28.428602

    • Related Report
      2020 Annual Research Report
    • Open Access / Int'l Joint Research
  • [Journal Article] APEGS法によるタンパク質パルミトイル化修飾の定量2021

    • Author(s)
      深田正紀、横井紀彦、深田優子
    • Journal Title

      電気泳動

      Volume: 65

    • NAID

      130008072916

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Forelimb movements evoked by optogenetic stimulation of the macaque motor cortex2020

    • Author(s)
      Watanabe H, Sano H, Chiken S, Kobayashi K, Fukata Y, Fukata M, Mushiake H, Nambu A
    • Journal Title

      Nat Commun

      Volume: 11 Issue: 1 Pages: 3253-3253

    • DOI

      10.1038/s41467-020-16883-5

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] A genetically encoded red fluorescence dopamine biosensor enables dual imaging of dopamine and norepinephrine2020

    • Author(s)
      Nakamoto Chihiro、Goto Yuhei、Tomizawa Yoko、Fukata Yuko、Fukata Masaki、Harpsoe Kasper、Gloriam David E.、Aoki Kazuhiro、Takeuchi Tomonori
    • Journal Title

      bioRxiv

      Volume: -

    • DOI

      10.1101/2020.05.25.115162

    • Related Report
      2020 Annual Research Report
    • Open Access / Int'l Joint Research
  • [Presentation] Trans-synaptic LGI1-ADAM22-MAGUK protein complex in synaptic functions and disorders2021

    • Author(s)
      Fukata Masaki、Fukata Yuko
    • Organizer
      SYNABS Symposium (Germany, Virtual meeting)
    • Related Report
      2021 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Acyl-PEGyl exchange gel-shift (APEGS) assay for palmitoylation quantification2020

    • Author(s)
      Fukata Masaki、Yokoi Norihiko、Fukata Yuko
    • Organizer
      第71回 日本電気泳動学会総会
    • Related Report
      2020 Annual Research Report
    • Invited
  • [Presentation] Synaptic function regulated by palmitate cycling on PSD-95 and trans-synaptic LGI1 and ADAM222020

    • Author(s)
      Fukata Masaki、Yuri Miyazaki、Yokoi Norihiko、Fukata Yuko
    • Organizer
      第43回日本分子生物学会年会
    • Related Report
      2020 Annual Research Report
    • Invited
  • [Book] 膜タンパク質工学ハンドブック2020

    • Author(s)
      平野瑶子、宮﨑裕理、横井紀彦、平田哲也、深田正紀、深田優子
    • Total Pages
      17
    • Publisher
      エヌ・ティー・エス
    • ISBN
      9784860435370
    • Related Report
      2020 Annual Research Report
  • [Remarks] 研究室ホームページ

    • URL

      https://www.nips.ac.jp/fukata/

    • Related Report
      2021 Annual Research Report 2020 Annual Research Report
  • [Remarks] プレスリリース 新たなてんかん治療戦略を提案

    • URL

      https://www.nips.ac.jp/release/2021/12/_adam22.html

    • Related Report
      2021 Annual Research Report
  • [Remarks] プレスリリース 新たなてんかん治療戦略を提案

    • URL

      https://www.amed.go.jp/news/release_20211215.html

    • Related Report
      2021 Annual Research Report
  • [Remarks] プレスリリース 新規赤色蛍光ドーパミンバイオセンサーの開発

    • URL

      https://www.nibb.ac.jp/press/2021/12/20.html

    • Related Report
      2021 Annual Research Report
  • [Remarks] プレスリリース:神経シナプス間の軸調整を担う分子群を発見―新たなてんかん病態を解明―

    • URL

      https://www.nips.ac.jp/release/2021/01/post_426.html

    • Related Report
      2020 Annual Research Report

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Published: 2020-04-28   Modified: 2022-12-28  

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