Identification of depalmitoylating enzymes

• Project/Area Number: 26291045
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Cell biology
• Research Institution: National Institute for Physiological Sciences
• Principal Investigator: FUKATA Masaki 生理学研究所, 分子細胞生理研究領域, 教授 (00335027)
• Research Collaborator: FUKATA Yuko 生理学研究所, 分子細胞生理研究領域, 准教授 (40416186) ; YOKOI Norihiko 生理学研究所, 分子細胞生理研究領域, 助教 (50710969) ; SEKIYA Atsushi ; MURAKAMI Tatsuro ; TAKAHASHI Naoki ; SUZUKI Yumi ; WATANABE Mie
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥16,640,000 (Direct Cost: ¥12,800,000、Indirect Cost: ¥3,840,000); Fiscal Year 2016: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2015: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2014: ¥7,280,000 (Direct Cost: ¥5,600,000、Indirect Cost: ¥1,680,000)
• Keywords: パルミトイル化修飾 / シナプス / 脱パルミトイル化酵素 / 脱パルミトイル化 / 脂質 / 蛋白質 / PSD-95 / ABHD17 / シナプス伝達 / 脳・神経 / 酵素 / 生理学 / パルミトイル化酵素 / 膜ドメイン / パルミトイル化 / 翻訳後修飾 / 脂質修飾

Outline of Final Research Achievements

Protein palmitoylation, the most common lipid modification, dynamically regulates neuronal protein localization and function. Its unique reversibility is conferred by DHHC-type palmitoyl acyl-transferases (palmitoylating enzymes) and still controversial palmitoyl-protein thioesterases (depalmitoylating enzymes). Here, we identified the membrane-anchored serine hydrolases, ABHD17A, 17B, and 17C, as the physiological PSD-95 depalmitoylating enzyme that regulates PSD-95 palmitoylation cycles in neurons. This study describes the first direct evidence for the neuronal depalmitoylating enzyme and provides a new aspect of the dynamic regulatory mechanisms of synaptic development and synaptic plasticity. In addition, our established APEGS assay, which provides unbiased and quantitative information about the palmitoylation state and dynamics, revealed the distinct regulatory mechanisms for synaptic palmitoylation.

Research Products

• [Int'l Joint Research] University of California, San Francisco(米国)
• [Int'l Joint Research] University of Helsinki(Finland)
• [Int'l Joint Research] DZNE(Germany)
• [Int'l Joint Research] University of South Florida(米国)
• [Int'l Joint Research] Hannover Medical School(Germany)
• [Int'l Joint Research] Institut Curie(France)
• [Journal Article] Astrocyte-mediated infantile-onset leukoencephalopathy mouse model (2017)
  • Author(s): Sugio S, Tohyama K, Oku S, Fujiyoshi K, Yoshimura T, Hikishima K, Yano R, Fukuda T, Nakamura M, Okano H, Watanabe M1, Fukata M, Ikenaka K, F Tanaka K
  • Journal Title: Glia Volume: 65 Issue: 1 Pages: 150-168
  • DOI: 10.1002/glia.23084
  • Peer Reviewed / Open Access
• [Journal Article] Coupling of a voltage-gated Ca2+ channel homologue with a plasma membrane H+-ATPase in yeast (2017)
  • Author(s): Cho T, Ishii-Kato A, Fukata Y, Nakayama Y, Iida K, Fukata M, Iida H
  • Journal Title: Genes Cells Volume: 22 Issue: 1 Pages: 94-104
  • DOI: 10.1111/gtc.12458
  • Peer Reviewed / Open Access
• [Journal Article] Secreted Metalloproteinase ADAMTS-3 Inactivates Reelin (2017)
  • Author(s): Ogino H, Hisanaga A, Kohno T, Kondo Y, Okumura K, Kamei T, Sato T, Asahara H, Tsuiji H, Fukata M, Hattori M
  • Journal Title: J Neurosci Volume: 37 Issue: 12 Pages: 3181-3191
  • DOI: 10.1523/jneurosci.3632-16.2017
  • Peer Reviewed / Open Access
• [Journal Article] The LGI1-ADAM22 protein complex in synaptic transmission and synaptic disorders (2017)
  • Author(s): Fukata Y, Yokoi N, Miyazaki Y, Fukata M
  • Journal Title: Neurosci Res Volume: 116 Pages: 39-45
  • DOI: 10.1016/j.neures.2016.09.011
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Epilepsy and synaptic proteins (2017)
  • Author(s): Fukata Y, Fukata M
  • Journal Title: Curr Opin Neurobiol Volume: 45 Pages: 1-8
  • DOI: 10.1016/j.conb.2017.02.001
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Identification of PSD-95 depalmitoylating enzymes (2016)
  • Author(s): Yokoi N*, Fukata Y*, Sekiya A, Murakami T, Kobayashi K, Fukata M
  • Journal Title: J Neurosci Volume: 36 Issue: 24 Pages: 6431-6444
  • DOI: 10.1523/jneurosci.0419-16.2016
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Dysfunctional ADAM22 implicated in progressive encephalopathy with cortical atrophy and epilepsy (2016)
  • Author(s): Muona M, Fukata Y, Anttonen AK, Laari A, Palotie A, Pihko H, Lönnqvist T, Valanne L, Somer M, Fukata M, Lehesjoki AE
  • Journal Title: Neurol Genet Volume: 2 Issue: 1
  • DOI: 10.1212/nxg.0000000000000046
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Local palmitoylation cycles and specialized membrane domain organization (2016)
  • Author(s): Fukata Y, Murakami T, Yokoi N, Fukata M
  • Journal Title: Curr Top Membr Volume: 77 Pages: 97-141
  • DOI: 10.1016/bs.ctm.2015.10.003
  • Peer Reviewed
• [Journal Article] The LGI1-ADAM22 protein complex directs synapse maturation through regulation of PSD-95 function (2015)
  • Author(s): Lovero KL, Fukata Y, Grangera AJ, Fukata M, Nicoll RA
  • Journal Title: Proc Natl Acad Sci USA Volume: 112 Issue: 30
  • DOI: 10.1073/pnas.1511910112
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Synaptic nanodomains generated by local palmitoylation cycles (2015)
  • Author(s): Masaki Fukata, Atsushi Sekiya, Tatsuro Murakami, Norihiko Yokoi, Yuko Fukata
  • Journal Title: Biochemical Society Transactions Volume: 43(2) Issue: 2 Pages: 199-204
  • DOI: 10.1042/bst20140238
  • Peer Reviewed
• [Journal Article] ELMOD2 is anchored to lipid droplets by palmitoylation and regulates ATGL recruitment (2015)
  • Author(s): Michitaka Suzuki, Tatsuro Murakami, Jinglei Cheng, Hiroyuki Kano, Masaki Fukata, and Toyoshi Fujimoto
  • Journal Title: MOLECULAR BIOLOGY OF THE CELL Volume: - Issue: 12 Pages: 2333-2342
  • DOI: 10.1091/mbc.e14-11-1504
  • Peer Reviewed / Open Access
• [Journal Article] The BAI1 regulates spatial learning and synaptic plasticity in the hippocampus. (2015)
  • Author(s): Dan Zhu, Chenchen Li, Andrew M. Swanson, Rosa M. Villalba, Jidong Guo, Zhaobin Zhang, Shannon Matheny, Tatsuro Murakami, Jason R. Stephenson, Sarah Daniel, Masaki Fukata, Randy A. Hall, Jeffrey J. Olson, Gretchen N. Neigh, Yoland Smith, Donald G. Rainnie, and Erwin G. Van Meir.
  • Journal Title: Journal of Clinical Investigation Volume: 125(4) Issue: 4 Pages: 1497-1508
  • DOI: 10.1172/jci74603
  • Peer Reviewed / Open Access
• [Journal Article] Chemical corrector treatment ameliorates increased seizure susceptibility in a mouse model of familial temporal lobe epilepsy. (2015)
  • Author(s): Yokoi N, Fukata Y, Kase D, Miyazaki T, Jaegle M, Ohkawa T, Takahashi N, Iwanari H, Mochizuki Y, Hamakubo T, Imoto K, Meijer D, Watanabe M, Fukata M
  • Journal Title: Nat Med Volume: 21 Issue: 1 Pages: 19-26
  • DOI: 10.1038/nm.3759
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Identification and characterization of GABAA receptor autoantibodies in autoimmune encephalitis (2014)
  • Author(s): Ohkawa T, Satake S, Yokoi N, Miyazaki Y, Ohshita T, Sobue G, Takashima H, Watanabe O, *Fukata Y, *Fukata M (*corresponding author).
  • Journal Title: J Neurosci Volume: 34 Issue: 24 Pages: 8151-8163
  • DOI: 10.1523/jneurosci.4415-13.2014
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Functional phylogenetic analysis of LGI proteins identifies an interaction motif crucial for myelination (2014)
  • Author(s): Kegel L, Jaegle M, Driegen S, Aunin E, Leslie K, Fukata Y, Watanabe M, Fukata M, Meijer D.
  • Journal Title: Development Volume: 141 Issue: 8 Pages: 1749-1756
  • DOI: 10.1242/dev.107995
  • Peer Reviewed
• [Journal Article] Non-Microtubular Localizations of Microtubule-Associated Protein 6 (MAP6) (2014)
  • Author(s): Gory-Faure S, Windscheid V, Brocard J, Montessuit S, Tsutsumi R, Denarier E, Fukata Y, Bosc C, Delaroche J, Collomb N, Fukata M, Martinou J, Pernet-Gallay K, Andrieux A.
  • Journal Title: PLoS One Volume: 9 Issue: 12 Pages: e114905-e114905
  • DOI: 10.1371/journal.pone.0114905
  • Peer Reviewed / Open Access
• [Presentation] Regulatory mechanisms for AMPA receptors through PSD-95 (2016)
  • Author(s): Masaki Fukata
  • Organizer: The 47th NIPS International Symposium “Decoding Synapses”
  • Place of Presentation: 岡崎コンファレンスセンター、愛知県岡崎市
  • Year and Date: 2016-10-26
  • Int'l Joint Research
• [Presentation] Regulators of glutamate receptors and epilepsy (2016)
  • Author(s): Masaki Fukata
  • Organizer: 第50回日本てんかん学会学術集会
  • Place of Presentation: グランシップ、静岡県静岡市
  • Year and Date: 2016-10-07
  • Invited
• [Presentation] Postsynaptic nanodomains regulated by local palmitoylation machinery (2016)
  • Author(s): Masaki Fukata, Norihiko Yokoi, Atsushi Sekiya, Tatsuro Murakami, Kenta Kobayashi, Yuko Fukata
  • Organizer: 10th Forum of Neuroscience (FENS)
  • Place of Presentation: Bella Center, Copenhagen, Denmark
  • Year and Date: 2016-07-02
  • Int'l Joint Research / Invited
• [Presentation] Molecular mechanisms of PSD95 (de)palmitoylation (2016)
  • Author(s): Masaki Fukata
  • Organizer: Invited Lecture at Medizinische Hochschule Hannover
  • Place of Presentation: Hannover, Germany
  • Invited
• [Presentation] Postsynaptic nanodomains regulated by local palmitoylation machinery (2016)
  • Author(s): Masaki Fukata
  • Organizer: Invited Lecture at Deutsches Zentrum fur Neurodegenerative Erkrankungen (DZNE)
  • Place of Presentation: Magdeburg, Germany
  • Invited
• [Presentation] The LGI1-ADAM22 protein complex in synaptic transmission and disorders (2016)
  • Author(s): Masaki Fukata
  • Organizer: Brain protein aging and dementia control: International workshop 2016
  • Place of Presentation: 名古屋大学医学部鶴友会館、愛知県名古屋市
  • Int'l Joint Research / Invited
• [Presentation] Postsynaptic nanodomain regulated by PSD-95 palmitoylation machinery (2015)
  • Author(s): Masaki Fukata
  • Organizer: Pacifichem 2015
  • Place of Presentation: Honolulu, Hawaii, USA
  • Year and Date: 2015-12-15
  • Int'l Joint Research / Invited
• [Presentation] Local palmitoylation cycles organize postsynaptic nanodomains (2015)
  • Author(s): Masaki Fukata
  • Organizer: 第38回日本分子生物学会年会/第88回日本生化学会大会
  • Place of Presentation: 神戸国際会議場・展示場（兵庫県神戸市中央区）
  • Year and Date: 2015-12-01
  • Invited
• [Presentation] Molecular pathogenic mechanisms of epilepsy caused by LGI1 mutations (2015)
  • Author(s): Norihiko Yokoi, Yuko Fukata, Daisuke Kase, Taisuke Miyazaki, Martin Jaegle, Keiji Imoto, Deis Meijer, Masahiko Watanabe, Masaki Fukata
  • Organizer: 45th annual meeting of the Society for Neuroscience
  • Place of Presentation: McCormick Place, Chicago, USA
  • Year and Date: 2015-10-17
  • Int'l Joint Research
• [Presentation] Exploration of depalmitoylating enzymes regulating bi-directional trafficking of small GTPase HRas (2015)
  • Author(s): Tatsuro Murakami, Atsushi Sekiya, Yuko Fukata, Masaki Fukata
  • Organizer: 第38回日本神経科学大会
  • Place of Presentation: 神戸国際会議場・展示場（兵庫県神戸市中央区）
  • Year and Date: 2015-07-28
• [Presentation] Role of LGI1-ADAM22 in synaptic function and disorders (2015)
  • Author(s): Masaki Fukata
  • Organizer: 第38回日本神経科学大会
  • Place of Presentation: 神戸国際会議場・展示場（兵庫県神戸市中央区）
  • Year and Date: 2015-07-28
  • Invited
• [Presentation] Regulatory mechanism for local palmitoylation cycles on PSD-95 (2015)
  • Author(s): Masaki Fukata
  • Organizer: FASEB Science Research Conference “Protein Lipidation, Signaling, and Membrane Domains”
  • Place of Presentation: Saxtons River, Vermont, USA
  • Year and Date: 2015-07-19
  • Int'l Joint Research / Invited
• [Presentation] Postsynaptic nanodomains organized by local palmitoylation machinery (2015)
  • Author(s): Yuko Fukata, Atsushi Sekiya, Tatsuro Murakami, Norihiko Yokoi, Kenta Kobayashi, Masaki Fukata
  • Organizer: FASEB Science Research Conference “Protein lipidation, Signaling, and Membrane Domains”
  • Place of Presentation: Saxtons River, Vermont, USA
  • Year and Date: 2015-07-19
  • Int'l Joint Research
• [Presentation] Stoichiometric analysis of palmitoylation cycles on PSD-95 (2015)
  • Author(s): Norihiko Yokoi, Atsushi Sekiya, Tatsuro Murakami, Yuko Fukata, Masaki Fukata
  • Organizer: FASEB Science Research Conference “Protein lipidation, Signaling, and Membrane Domains”
  • Place of Presentation: Saxtons River, Vermont, USA
  • Year and Date: 2015-07-19
  • Int'l Joint Research
• [Presentation] Characterization of a mouse model with genetic deletion of DHHC2 palmitoyl acyl transferase (2015)
  • Author(s): Tatsuro Murakami, Atsushi Sekiya, Manabu Abe, Kenji Sakimura, Yuko Fukata, Masaki Fukata
  • Organizer: FASEB Science Research Conference “Protein lipidation, Signaling, and Membrane Domains”
  • Place of Presentation: Saxtons River, Vermont, USA
  • Year and Date: 2015-07-19
  • Int'l Joint Research
• [Presentation] Postsynaptic nanodomains organized by PSD-95 palmitoylation machinery (2015)
  • Author(s): Masaki Fukata
  • Organizer: 第67回日本細胞生物学会大会
  • Place of Presentation: タワーホール船堀（東京都江戸川区）
  • Year and Date: 2015-06-30
  • Invited
• [Presentation] Specialized membrane nanodomain organized by lipid modification (2015)
  • Author(s): Fukata M, Sekiya A, Murakami T, Fukata Y
  • Organizer: 第92回日本生理学会大会
  • Place of Presentation: 神戸国際会議場・展示場（兵庫県神戸市中央区）
  • Year and Date: 2015-03-21 – 2015-03-23
  • Invited
• [Presentation] てんかん原因遺伝子LGI1の先天的および後天的分子異常による脳機能障害 (2014)
  • Author(s): 深田優子､横井紀彦、深田正紀
  • Organizer: 第37回日本分子生物学会年会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市西区）
  • Year and Date: 2014-11-25 – 2014-11-27
• [Presentation] Synaptic organization regulated by palmitoylating and depalmitoylating enzymes of PSD-95 (2014)
  • Author(s): Fukata M
  • Organizer: 44th annual meeting of the Society for Neuroscience
  • Place of Presentation: Washington, DC, USA
  • Year and Date: 2014-11-15 – 2014-11-19
  • Invited
• [Presentation] Pathological roles of autoantibodies to synaptic proteins in encephalitic (2014)
  • Author(s): Fukata Y., Ohkawa T., Satake S., Yokoi N., Watanabe M., Fukata M.
  • Organizer: 44th annual meeting of the Society for Neuroscience
  • Place of Presentation: Washington, DC, USA
  • Year and Date: 2014-11-15 – 2014-11-19
• [Presentation] ポストシナプスに局在する脱パルミトイル化酵素の同定と性状解析 (2014)
  • Author(s): 関谷敦志、村上達郎、小林憲太、深田優子、深田正紀
  • Organizer: 第87回日本生化学会大会
  • Place of Presentation: 国立京都国際会館（京都府京都市左京区）
  • Year and Date: 2014-10-15 – 2014-10-18
• [Presentation] LGI1分子の役割と自己抗体の作用機序 (2014)
  • Author(s): 深田正紀、大川都史香、横井紀彦、深田優子
  • Organizer: 第48回てんかん学会学術集会
  • Place of Presentation: 京王プラザホテル（東京都新宿区）
  • Year and Date: 2014-10-02 – 2014-10-03
  • Invited
• [Presentation] Postsynaptic nanodomains generated by local palmitoylation cycles (2014)
  • Author(s): Fukata M
  • Organizer: Biochemical Society Focused Meeting
  • Place of Presentation: Edinburgh, UK
  • Year and Date: 2014-09-12 – 2014-09-14
  • Invited
• [Presentation] Molecular mechanisms of LGI1 mutation-related epilepsy and new strategy for human epilepsy (2014)
  • Author(s): Yokoi N., Fukata Y., Kase D., Miyazaki T., Jaegle M., Imoto K., Meijer D., Watanabe M., Fukata M.
  • Organizer: 第37回日本神経科学大会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市西区）
  • Year and Date: 2014-09-11 – 2014-09-13
• [Presentation] Exploration of depalmitoylating enzymes regulating bi-directional trafficking of small GTPase HRas (2014)
  • Author(s): Murakami T, Sekiya A, Fukata Y, Fukata M
  • Organizer: 第37回日本神経科学大会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市西区）
  • Year and Date: 2014-09-11 – 2014-09-13
• [Presentation] 免疫性脳炎:自己抗体によるｼﾅﾌﾟｽ機能異常 (2014)
  • Author(s): 深田正紀
  • Organizer: 第44回(2014)新潟神経学夏期セミナー
  • Place of Presentation: 新潟大学脳研究所 （新潟県新潟市中央区）
  • Year and Date: 2014-08-01 – 2014-08-02
  • Invited
• [Book] メンブレントラフィック (2016)
  • Author(s): 深田優子、横井紀彦、宮崎裕理、深田正紀
  • Publisher: 化学同人
• [Book] 細胞工学 (2015)
  • Author(s): 横井紀彦、深田正紀、深田優子
  • Publisher: 秀潤社
• [Book] 細胞工学 (2015)
  • Author(s): 横井紀彦、深田優子、深田正紀
  • Total Pages: 85
  • Publisher: 学研メディカル秀潤社
• [Remarks] シナプス蛋白質PSD-95の局在を調節する酵素の同定
  • URL: http://www.nips.ac.jp/nips_research/2016/06/psd-95.html
• [Remarks] 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] 生理学研究所 プレスリリース
  • URL: http://www.nips.ac.jp/release/2014/12/post_285.html
• [Remarks] ライフサイエンス新着論文レビュー
  • URL: http://first.lifesciencedb.jp/archives/9607