S-アシル化修飾ゾーンとシナプス機能

• Project Area: Toward an integrative understanding of functional zones in organelles
• Project/Area Number: 18H04873
• Research Category: Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)
• Allocation Type: Single-year Grants
• Research Institution: National 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): 2018-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥7,410,000 (Direct Cost: ¥5,700,000、Indirect Cost: ¥1,710,000); Fiscal Year 2019: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000); Fiscal Year 2018: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000)
• Keywords: S-アシル化修飾 / タンパク質 / ZDHHCタンパク質 / ABHD17 / シナプス / ゾーン / 脂質 / 酵素 / S-アシル化 / ZDHHC2

Outline of Annual Research Achievements

S-アシル化脂質修飾は、酵母から動・植物まで保存された普遍的な翻訳後修飾で、タンパク質の輸送や機能を制御する。S-アシル化反応は可逆反応であり、アシル化、脱アシル化両反応のバランスが外界刺激により制御されている。多種多様なS-アシル化タンパク質は、様々なオルガネラ膜や細胞膜に特異性をもって局在化するが、興味深いことに、私共が単離したS-アシル化関連酵素群も、小胞体やゴルジ体のみならず、エンドソームや細胞膜といった多様な細胞内局在を示す。そこで、私共は“タンパク質合成直後の小胞体やゴルジ体における選別輸送に加えて、細胞膜のような最終到達地においても、S-アシル化酵素と脱S-アシル化酵素が協調して「S-アシル化修飾ゾーン」を形成し、タンパク質の動的な局在制御を担っている”という仮説を検証する。本研究では、神経細胞のシナプス膜をモデルとして、その形成と機能発現における「S-アシル化修飾ゾーン」の役割を解明する。2019年度は、特異性を重視した免疫沈降法により脱アシル化酵素ABHD17の結合タンパク質を多数同定した。また、ミトコンドリアに局在化させた脱S-アシル化プローブ(mitoDPP)と私共の脱S-アシル化酵素ライブラリーを活用して、ミトコンドリアにおける脱S-アシル化酵素としてABHD10を同定した(Bryan Dickinson 博士(シカゴ大)との国際共同研究、Nat Chem Biol誌に発表)。さらに、私共のS-アシル化酵素ライブラリーを活用した国際共同研究により、CCR5(HIV-1ウイルスの受容体)のS-アシル化酵素(ZDHHC3,7)を同定し、その輸送機構を解明した(Franck Perez博士（キュリー研究所）との国際共同研究、Science Advances誌に発表)。

Research Progress Status

令和元年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

令和元年度が最終年度であるため、記入しない。

Research Products

• [Int'l Joint Research] UCSF/Chicago University(米国)
• [Int'l Joint Research] Institut Curie(フランス)
• [Int'l Joint Research] DZNE(ドイツ)
• [Int'l Joint Research] UCL Institute of Neurology(英国)
• [Int'l Joint Research] University of Helsinki(フィンランド)
• [Int'l Joint Research]
• [Int'l Joint Research] University of Edinburgh(英国)
• [Int'l Joint Research] University of Chicago/University of California, San Francisco/University of Michigan(米国)
• [Int'l Joint Research] DZNE(ドイツ)
• [Int'l Joint Research] Institute of Science and Technology(オーストリア)
• [Journal Article] The extracellular domain of angulin-1 and palmitoylation of its cytoplasmic region are required for angulin-1 assembly at tricellular contacts (2020)
  • Author(s): Yukako Oda, Taichi Sugawara, Yuko Fukata, Yasushi Izumi, Tetsuhisa Otani, Tomohito Higashi, Masaki Fukata, Mikio Furuse
  • Journal Title: Journal of Biological Chemistry Volume: 295 Issue: 13 Pages: 4289-4302
  • DOI: 10.1074/jbc.ra119.010491
  • Peer Reviewed / Open Access
• [Journal Article] Human Cerebrospinal Fluid Monoclonal LGI1 Autoantibodies Increase Neuronal Excitability (2020)
  • Author(s): Kornau Hans‐Christian、Kreye Jakob、Stumpf Alexander、Fukata Yuko、Parthier Daniel、Sammons Rosanna P.、Imbrosci Barbara、Kurpjuweit Sarah、Kowski Alexander B.、Fukata Masaki、Pruss Harald、Schmitz Dietmar
  • Journal Title: Annals of Neurology Volume: 87 Issue: 3 Pages: 405-418
  • DOI: 10.1002/ana.25666
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Dynamic palmitoylation controls the microdomain localization of the DKK1 receptors CKAP4 and LRP6 (2019)
  • Author(s): Sada Ryota、Kimura Hirokazu、Fukata Yuko、Fukata Masaki、Yamamoto Hideki、Kikuchi Akira
  • Journal Title: Science Signaling Volume: 12 Issue: 608 Pages: 9519-9519
  • DOI: 10.1126/scisignal.aat9519
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] ABHD10 is an S-depalmitoylase affecting redox homeostasis through peroxiredoxin-5 (2019)
  • Author(s): Cao Yang、Qiu Tian、Kathayat Rahul S.、Azizi Saara-Anne、Thorne Anneke K.、Ahn Daniel、Fukata Yuko、Fukata Masaki、Rice Phoebe A.、Dickinson Bryan C.
  • Journal Title: Nature Chemical Biology Volume: 15 Issue: 12 Pages: 1232-1240
  • DOI: 10.1038/s41589-019-0399-y
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Targeting CCR5 trafficking to inhibit HIV-1 infection (2019)
  • Author(s): Boncompain Gaelle、Herit Floriane、Tessier Sarah、Lescure Aurianne、Del Nery Elaine、Gestraud Pierre、Staropoli Isabelle、Fukata Yuko、Fukata Masaki、Brelot Anne、Niedergang Florence、Perez Franck
  • Journal Title: Science Advances Volume: 5 Issue: 10
  • DOI: 10.1126/sciadv.aax0821
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Systematic Screening of Depalmitoylating Enzymes and Evaluation of Their Activities by the Acyl-PEGyl Exchange Gel-Shift (APEGS) Assay (2019)
  • Author(s): Kanadome T, Yokoi N, Fukata Y, Fukata M.
  • Journal Title: Methods Mol Biol Volume: 印刷中 Pages: 83-98
  • DOI: 10.1007/978-1-4939-9532-5_7
  • ISBN: 9781493995318, 9781493995325
  • Peer Reviewed
• [Journal Article] Limbic Encephalitis in a Cat with Hippocampal Necrosis, putatively associated with DCC (deleted in colorectal cancer; Netrin-1 Receptor) Antibodies (2019)
  • Author(s): Hasegawa D, Ohnishi Y, Koyama E, Matsunaga S, Ohtani S, Nakanishi A, Shiga T, Chambers JK, Uchida K, Yokoi N, Fukata Y, Fukata M.
  • Journal Title: J Vet Intern Med Volume: 印刷中 Issue: 3 Pages: 1440-1445
  • DOI: 10.1111/jvim.15492
  • Peer Reviewed
• [Journal Article] Structural basis of epilepsy-related ligand-receptor complex LGI1-ADAM22 (2018)
  • Author(s): Yamagata Atsushi、Miyazaki Yuri、Yokoi Norihiko、Shigematsu Hideki、Sato Yusuke、Goto-Ito Sakurako、Maeda Asami、Goto Teppei、Sanbo Makoto、Hirabayashi Masumi、Shirouzu Mikako、Fukata Yuko、Fukata Masaki、Fukai Shuya
  • Journal Title: Nature Communications Volume: 9 Issue: 1 Pages: 1546-1546
  • DOI: 10.1038/s41467-018-03947-w
  • Peer Reviewed / Open Access
• [Journal Article] Long-term clinical follow-up of a patient with non-paraneoplastic cerebellar ataxia associated with anti-mGluR1 autoantibodies (2018)
  • Author(s): Yoshikura Nobuaki、Kimura Akio、Fukata Masaki、Fukata Yuko、Yokoi Norihiko、Harada Naoko、Hayashi Yuichi、Inuzuka Takashi、Shimohata Takayoshi
  • Journal Title: Journal of Neuroimmunology Volume: 319 Pages: 63-67
  • DOI: 10.1016/j.jneuroim.2018.04.001
  • Peer Reviewed
• [Presentation] Synapse maturation regulated by palmitate cycling on PSD-95 and trans-synaptic LGI1 and ADAM22 (2019)
  • Author(s): Fukata Masaki
  • Organizer: CFC seminar series Spring
  • Int'l Joint Research / Invited
• [Presentation] The LGI1-ADAM22 protein complex in synaptic transmission and synaptic disorders (2019)
  • Author(s): Fukata Masaki
  • Organizer: 2019 Korea-Yonsei-NIPS International Joint Symposium
  • Int'l Joint Research / Invited
• [Presentation] シナプス成熟機構とその破綻による病態機構 (2019)
  • Author(s): 深田正紀
  • Organizer: 第92回日本生化学会大会
  • Invited
• [Presentation] Physiological roles of trans-synaptic LGI1-ADAM22-MAGUK complex (2019)
  • Author(s): Fukata Yuko、Hirano Yoko、Inahashi Hiroki、Miyazaki Yuri、Yokoi Norihiko、Sanbo Makoto、Goto Teppei、Hirabayashi Masumi, Fukata Masaki
  • Organizer: Neuroscience Meeting SfN 2019
  • Int'l Joint Research
• [Presentation] Binding mode and physiological role of epilepsy-related ligand/receptor LGI1-ADAM22 complex based on structural analysis (2018)
  • Author(s): Miyazaki Y, Yamagata A, Yokoi N, Fukata Y, Fukai S, Fukata M
  • Organizer: Neuroscience 2018
  • Int'l Joint Research
• [Presentation] Synapse maturation regulated by palmitate cycling on PSD-95 and trans-synaptic LGI1 and ADAM22 (2018)
  • Author(s): Fukata Y, Yokoi N, Hirata T, Miyazaki Y, Hirano Y, Fukata M
  • Organizer: 2018 ASCB | EMBO Annual Meeting
  • Int'l Joint Research
• [Presentation] Structural basis of epilepsy-related ligand-receptor complex LGI1-ADAM22 (2018)
  • Author(s): Yamagata A, Miyazaki Y, Shigematsu H, Shirouzu M, Fukata Y, Fukata M, Fukai S
  • Organizer: 日本生物物理学会第56回年会
• [Presentation] てんかんの原因となる蛋白質複合体 LGI1-ADAM22 の構造基盤 (2018)
  • Author(s): 山形敦史、 宮崎裕理、深田優子、深田正紀、深井周也
  • Organizer: 第41回日本分子生物学会年会
• [Presentation] 抗mGluR1 抗体陽性小脳性運動失調症2症例の臨床像の検討 (2018)
  • Author(s): 吉倉延亮、安井敬三、木村暁夫、横井紀彦、深田優子、深田正紀、下畑享良
  • Organizer: 第30回日本神経免疫学会学術集会
• [Remarks] 研究室ホームページ
  • URL: https://www.nips.ac.jp/fukata/
• [Remarks] 自然科学研究機構 生理学研究所 生体膜研究部門ホームページ
  • URL: http://www.nips.ac.jp/fukata/
• [Remarks] てんかんの原因タンパク質が神経細胞間の橋渡しをする仕組みを解明
  • URL: http://www.nips.ac.jp/release/2018/04/post_363.html