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Elucidation of the function of novel actin-binding factors in neutrophil phagocytosis and extracellular trap formation

Research Project

Project/Area Number 19K07084
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 47030:Pharmaceutical hygiene and biochemistry-related
Research InstitutionOkayama University

Principal Investigator

ABE TADASHI  岡山大学, 医学部, 技術専門員 (60423282)

Co-Investigator(Kenkyū-buntansha) 竹居 孝二  岡山大学, 医歯薬学域, 教授 (40322226)
山田 浩司  岡山大学, 医歯薬学域, 准教授 (80325092)
Project Period (FY) 2019-04-01 – 2022-03-31
Project Status Completed (Fiscal Year 2021)
Budget Amount *help
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2021: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Keywords細胞外トラップ / ダイナミン / アクチン
Outline of Research at the Start

体内の細菌の侵入を察知した好中球は、細胞膜とアクチン骨格をダイナミックに再構成し、形態を変化させて殺菌行動に備える。次いで貪食するか、細胞外に放出したクロマチン網で細菌を捕らえ殺菌する。我々は、好中球の機能低下を示すダイナミンの疾患変異解析から、好中球のアクチン再構成に必須な機構(ダイナミンクロスブリッジ)を発見した。ダイナミンは、細胞膜とアクチン再構成を協奏的に制御し殺菌に寄与する可能性が高い。本研究は、「細胞外トラップ」と貪食において、ダイナミンにより膜とアクチン再構成がどのように制御されるのかを明らかにし、好中球殺菌機構の全貌にせまる。

Outline of Final Research Achievements

Neutrophils play an essential role in the destruction of bacteria in innate immune system. In the process of killing pathogens, neutrophils drastically change their cell shape with accompanying the rearrangement of actin cytoskeleton. We found that expressing dynamin 2 K562E mutant, one of the pathogenic mutations in Charcot-Marie-Tooth disease in cells leads to aberrant actin clusters and stress fibers. The effect of this mutant on actin fibers was analyzed in vitro. Recombinant dynamin 2 K562E showed lower self-assembly ability and membrane binding ability than that of dynamin 2 wildtype. Although dynamin K562E directly bundled actin filaments, the formed bundles showed much less ability to bind to the lipid membranes as compared to dynamin 2 wildtype. In conclusion, dynamin 2-mediated interactions between actin and membranes are critical for actin bundle formation in neutrophil functions.

Academic Significance and Societal Importance of the Research Achievements

好中球は細胞膜とアクチン骨格をダイナミックに再構成し、形態を変化させて体内に侵入した細菌の殺菌行動に備える。次いで貪食するか、細胞外に放出したクロマチン網で細菌を捕らえ殺菌する。このクロマチン網は、細胞外トラップと呼ばれ、強力な殺菌手段である。最近、細胞外トラップが自己免疫疾患、がん転移、血栓の過形成への関与が報告され、その形成制御が課題である。本研究は、好中球の貪食及び細胞外トラップ形成に関わる細胞膜とアクチン骨格の再構成機構を解析する研究である。得られる知見は、好中球の殺菌機構の解明のみならず、近年明らかになった好中球細胞トラップ由来の数々の炎症の治療戦略に大きく寄与すると考えられる。

Report

(4 results)
  • 2021 Annual Research Report   Final Research Report ( PDF )
  • 2020 Research-status Report
  • 2019 Research-status Report
  • Research Products

    (22 results)

All 2022 2021 2020 2019

All Journal Article (9 results) (of which Int'l Joint Research: 4 results,  Peer Reviewed: 9 results,  Open Access: 9 results) Presentation (13 results)

  • [Journal Article] JRAB/MICAL-L2 undergoes liquid-liquid phase separation to form tubular recycling endosomes2021

    • Author(s)
      Sakane Ayuko、Yano Taka-aki、Uchihashi Takayuki、Horikawa Kazuki、Hara Yusuke、Imoto Issei、Kurisu Shusaku、Yamada Hiroshi、Takei Kohji、Sasaki Takuya
    • Journal Title

      Communications Biology

      Volume: 4 Issue: 1 Pages: 551-551

    • DOI

      10.1038/s42003-021-02080-7

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Imaging‐based evaluation of pathogenicity by novel DNM2 variants associated with centronuclear myopathy2021

    • Author(s)
      Fujise Kenshiro、Okubo Mariko、Abe Tadashi、Yamada Hiroshi、Takei Kohji、Nishino Ichizo、Takeda Tetsuya、Noguchi Satoru
    • Journal Title

      Human Mutation

      Volume: 43 Issue: 2 Pages: 169-179

    • DOI

      10.1002/humu.24307

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Dynamin 2 and BAR domain protein pacsin 2 cooperatively regulate formation and maturation of podosomes2021

    • Author(s)
      Li Jianzhen、Fujise Kenshiro、Wint Haymar、Senju Yosuke、Suetsugu Shiro、Yamada Hiroshi、Takei Kohji、Takeda Tetsuya
    • Journal Title

      Biochemical and Biophysical Research Communications

      Volume: 571 Pages: 145-151

    • DOI

      10.1016/j.bbrc.2021.07.041

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Mutant BIN1-Dynamin 2 complexes dysregulate membrane remodeling in the pathogenesis of centronuclear myopathy2021

    • Author(s)
      Fujise K., Okubo M., Abe T., Yamada H., Nishino I., Noguchi S., Takei K., Takeda T.
    • Journal Title

      Journal of Biological Chemistry

      Volume: 296 Pages: 100077-100077

    • DOI

      10.1074/jbc.ra120.015184

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Internalization of AMPA-type glutamate receptor in the MIN6 pancreatic beta-cell line2020

    • Author(s)
      The Mon La, Yamada, H., Seiriki, S., Li, S.A., Fujise, K., Katsumi, N., Abe, T., Watanabe, M., Takei, K.
    • Journal Title

      Cell Struct. Func.

      Volume: 45 Issue: 2 Pages: 121-130

    • DOI

      10.1247/csf.20020

    • NAID

      130007889517

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Dynamin 1 is important for microtubule organisation and stabilisation in glomerular podocytes2020

    • Author(s)
      The Mon La , Tachibana, H., Li, S.A., Abe, T., Seiriki, S., Nagaoka, H., Takashima, E., Takeda, T., Ogawa, D., Makino, S., Asanuma, K., Watanabe, M., Tian, X., Ishibe, S., Sakane, A., Sasaki, T., Wada, J., Takei, K., Yamada, H.
    • Journal Title

      FASEB Journal

      Volume: 34 Issue: 12 Pages: 16449-16463

    • DOI

      10.1096/fj.202001240rr

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] ATP6AP2 variant impairs CNS development and neuronal survival to cause fulminant neurodegeneration2019

    • Author(s)
      Takuo Hirose, Alfredo Cabrera-Socorro, David Chitayat, Thomas Lemonnier, Olivier Feraud, Carmen Cifuentes-Diaz, Nicolas Gervasi, Cedric Mombereau, Tanay Ghosh, Loredana Stoica, Al Bacha Jeanne d'arc, Hiroshi Yamada et al.
    • Journal Title

      Journal of Clinical Investigation

      Volume: 130 Issue: 5 Pages: 2145-2162

    • DOI

      10.1172/jci79990

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] A Novel Membrane Fission Mechanism by Dynamin Complex: Clusterase Model2019

    • Author(s)
      竹居 孝二,山田 浩司,竹田 哲也
    • Journal Title

      Seibutsu Butsuri

      Volume: 59 Issue: 5 Pages: 255-261

    • DOI

      10.2142/biophys.59.255

    • NAID

      130007718913

    • ISSN
      0582-4052, 1347-4219
    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Initial phospholipid-dependent Irgb6 targeting to Toxoplasma gondii vacuoles mediates host defense.2019

    • Author(s)
      Lee, Y., Yamada, H., Pradipta, A., Ma, J.S., Okamoto, M., Nagaoka, H., Takashima, E., Standley, D.M., Sasai, M., Takei, K., Yamamoto, M.
    • Journal Title

      Life Science Alliance

      Volume: 3 Issue: 1 Pages: 000-000

    • DOI

      10.26508/lsa.201900549

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] 骨格筋細胞分化におけるMTM1/Myotubularin の機能解析2022

    • Author(s)
      田原史也, 藤瀬賢志郎, 山田浩司, 竹居孝二, 竹田哲也
    • Organizer
      生体運動研究合同班会議 2022
    • Related Report
      2021 Annual Research Report
  • [Presentation] ポドサイトにおけるダイナミン2によるアクチン制御にはダイナミン2の適切な自己重合と膜との相互作用が必要である2022

    • Author(s)
      山田浩司
    • Organizer
      第6回ポドサイト研究会
    • Related Report
      2021 Annual Research Report
  • [Presentation] 分化ポドサイトにおけるダイナミン1の機能2022

    • Author(s)
      竹居孝二
    • Organizer
      第6回ポドサイト研究会
    • Related Report
      2021 Annual Research Report
  • [Presentation] ダイナミン2の自己重合と膜との相互作用は糸球体ポドサイトのアクチン制御に重要である2021

    • Author(s)
      濱崎英理子, 安岡宏樹, 和木田夏輝, 阿部匡史, 竹田哲也, 竹居孝二, 山田浩司
    • Organizer
      第62回日本生化学会中国・四国支部例会
    • Related Report
      2021 Annual Research Report
  • [Presentation] 糸球体ポドサイトからのグルタミン酸の放出と開口放出関連タンパクの探索2021

    • Author(s)
      安岡宏樹, 西井尚子, 原田結加, 宮地孝明, 阿部匡史, 竹田哲也, 和田淳, 竹居孝二, 山田浩司
    • Organizer
      第62回日本生化学会中国・四国支部例会
    • Related Report
      2021 Annual Research Report
  • [Presentation] ダイナミン1は微小管の配向を調節しTRPV2の細胞膜移行を制御する2021

    • Author(s)
      籔彩夏, 安岡宏樹, 片野坂友紀, 阿部匡史, 竹田哲也, 竹居孝二, 山田浩司
    • Organizer
      第62回日本生化学会中国・四国支部例会
    • Related Report
      2021 Annual Research Report
  • [Presentation] 糸球体足細胞(ポドサイト)におけるダイナミンによる微小管制御と形態形成2021

    • Author(s)
      山田浩司
    • Organizer
      第94回日本生化学会大会
    • Related Report
      2021 Annual Research Report
  • [Presentation] Dynamin 2 and BAR domain protein pacsin2 cooperatively regulate formation and maturation of podosomes2021

    • Author(s)
      Jianzhen Li, Kenshiro Fujise, Haymar Wint, Yosuke Senju, Shiro Suetsugu, Hiroshi Yamada, Kohji Takei, Tetsuya Takeda
    • Organizer
      第44回日本分子生物学会年会
    • Related Report
      2021 Annual Research Report
  • [Presentation] Unveiling function of a BAR domain protein Pacsin 2 in cancer cell migration and invasion2021

    • Author(s)
      Haymar Wint, Jianzhen Li, Kenshiro Fujise, Hiroshi Yamada, Kohji Takei, Tetsuya Takeda
    • Organizer
      第44回日本分子生物学会年会
    • Related Report
      2021 Annual Research Report
  • [Presentation] 腎糸球体ポドサイトにおけるアンフィファイジン1の機能2019

    • Author(s)
      山田浩司, The Mon La, 竹田哲也, 阿部匡史, 淺沼克彦, 竹居孝二
    • Organizer
      第92回日本生化学会大会
    • Related Report
      2019 Research-status Report
  • [Presentation] 腎糸球体ポドサイトにおけるダイナミンイソフォームの局在と機能2019

    • Author(s)
      阿部匡史, The Mon La, 橘 洋美, 竹田哲也, 竹居孝二, 山田浩司
    • Organizer
      第92回日本生化学会大会
    • Related Report
      2019 Research-status Report
  • [Presentation] ダイナミン GTP アーゼはアクチン線維の束化と分散を機械的に制御する2019

    • Author(s)
      竹居孝二 , テ モン ラ, 阿部匡史, 竹田哲也, 藤原郁子, 成田哲博
    • Organizer
      第57回日本生物物理学会年会
    • Related Report
      2019 Research-status Report
  • [Presentation] Amphiphysin 1 is important for actin cytoskeletal regulation with synaptopodin in glomerular podocytes2019

    • Author(s)
      The Mon La, Tadashi Abe, Masayuki Morita, Eizo Takashima, Tetsuya Takeda, Katsuhiko Asanuma, Takei Kohji, Hiroshi Yamada
    • Organizer
      第42回日本分子生物学会年会
    • Related Report
      2019 Research-status Report

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Published: 2019-04-18   Modified: 2023-01-30  

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