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Elucidation of the regulatory mechanism of integrin-harboring vesicles for the suppression of pathogenic vesicles

Research Project

Project/Area Number 20K07331
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 48040:Medical biochemistry-related
Research InstitutionKansai Medical University

Principal Investigator

KONDO Naoyuki  関西医科大学, 医学部, 講師 (30570840)

Project Period (FY) 2020-04-01 – 2024-03-31
Project Status Completed (Fiscal Year 2023)
Budget Amount *help
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2023: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2022: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
Fiscal Year 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2020: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
Keywordsインテグリン / 小胞輸送 / 一分子計測 / LFA1 / inside-out / outside-in / リンパ球 / LFA-1 / Rab8 / Rabin8 / 超解像イメージング / 全反射顕微鏡 / 質量分析 / ウイルス / 細胞外小胞
Outline of Research at the Start

インテグリン (ITG) は生体内における細胞の接着・動態を司る.細胞接着面でのITG制御機構は長年謎であった. 申請者は接着面でのリガンド結合の一分子計測に世界で初めて成功し, 一過性のITG-リガンド結合の繰り返しが接着を制御することを見出した.一方, 結合の素早いON/OFFの制御機構は不明であった.本研究ではITGを含有小胞の膜輸送/取込/排出のバランスを統御する制御因子の働きがITG機能を時空間的に制御するという仮説の基に, 新規ITG小胞含有因子の同定と高速撮像手法を用いた動態解析を進め, 接着制御/小胞排出の制御機構の全容解明と, その知識の臨床応用への橋渡しを目指す.

Outline of Final Research Achievements

Leukocyte integrin LFA1, a causative molecule for immune-related disease, plays a vital role in cell-cell interactions; however, how LFA1 accumulates on the cell contact surface has remained elusive. In this study, we discovered for the first time that LFA1 accumulation was induced by the binding of LFA1 to its ligand ICAM1 in a positive-feedback manner. This ligand binding-dependent signaling promoted the formation of LFA1-containing vesicles, which colocalized and cotrafficked with Rab8. Deletion of Rab8 decreased the accumulation of LFA1 at the contact surface and LFA1-dependent cell adhesiveness in lymphocytes. Furthermore, ligand-dependent signaling promoted the accumulation and activation of Rabin8, an activator of Rab8, at the contact surface. Based on these results, we established a novel model for LFA1 transport and accumulation in lymphocyte adhesion.

Academic Significance and Societal Importance of the Research Achievements

白血球による免疫シナプス形成を介した細胞間相互作用や, ホーミングにおける血管内皮細胞に対する白血球の即座の接着において, これまでどのようにしてLFA1が素早く接着面に蓄積し接着を誘導するのかは不明であったが, LFA1-ICAM1結合に誘導される正の協同性を伴うLFA1蓄積経路の存在の解明により, そのLFA1制御メカニズムの一端が明らかになった. また, LFA1輸送におけるRabin8-Rab8経路の関与の解明は新規免疫関連疾患制御薬剤の開発や,インテグリンを含んで排出されるがん転移を担う細胞外小胞やウイルス等の産生・輸送制御法の開発にも繋がることが期待される.

Report

(5 results)
  • 2023 Annual Research Report   Final Research Report ( PDF )
  • 2022 Research-status Report
  • 2021 Research-status Report
  • 2020 Research-status Report
  • Research Products

    (32 results)

All 2023 2022 2021 2020

All Journal Article (11 results) (of which Int'l Joint Research: 4 results,  Peer Reviewed: 10 results,  Open Access: 9 results) Presentation (21 results) (of which Int'l Joint Research: 1 results)

  • [Journal Article] Distinct bidirectional regulation of LFA1 and α4β7 by Rap1 and integrin adaptors in T?cells under shear flow2023

    • Author(s)
      Kamioka Yuji、Ueda Yoshihiro、Kondo Naoyuki、Tokuhiro Keizo、Ikeda Yoshiki、Bergmeier Wolfgang、Kinashi Tatsuo
    • Journal Title

      Cell Reports

      Volume: 42 Issue: 6 Pages: 112580-112580

    • DOI

      10.1016/j.celrep.2023.112580

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Characterization of cytoskeletal and structural effects of INF2 variants causing glomerulopathy and neuropathy2023

    • Author(s)
      Ueda Hiroko、Tran Quynh Thuy Huong、Tran Linh Nguyen Truc、Higasa Koichiro、Ikeda Yoshiki、Kondo Naoyuki、Hashiyada Masaki、Sato Chika、Sato Yoshinori、Tsukaguchi Hiroyasu
    • Journal Title

      Scientific Reports

      Volume: 13 Issue: 1 Pages: 12003-12003

    • DOI

      10.1038/s41598-023-38588-7

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Thymocyte Development of Humanized Mice Is Promoted by Interactions with Human-Derived Antigen Presenting Cells upon Immunization2023

    • Author(s)
      Fukuhara Takataro、Ueda Yoshihiro、Lee Sung-Il、Odaka Tokifumi、Nakajima Shinsuke、Fujisawa Jun-Ichi、Okuma Kazu、Naganuma Makoto、Okazaki Kazuichi、Kondo Naoyuki、Kamioka Yuji、Matsumoto Mitsuru、Kinashi Tatsuo
    • Journal Title

      International Journal of Molecular Sciences

      Volume: 24 Issue: 14 Pages: 11705-11705

    • DOI

      10.3390/ijms241411705

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Rap1 organizes lymphocyte front-back polarity via RhoA signaling and talin12023

    • Author(s)
      Ueda Yoshihiro、Higasa Koichiro、Kamioka Yuji、Kondo Naoyuki、Horitani Shunsuke、Ikeda Yoshiki、Bergmeier Wolfgang、Fukui Yoshinori、Kinashi Tatsuo
    • Journal Title

      iScience

      Volume: 26 Issue: 8 Pages: 107292-107292

    • DOI

      10.1016/j.isci.2023.107292

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] The critical role of Rap1-GAPs Rasa3 and Sipa1 in T cells for pulmonary transit and egress from the lymph nodes2023

    • Author(s)
      Horitani Shunsuke、Ueda Yoshihiro、Kamioka Yuji、Kondo Naoyuki、Ikeda Yoshiki、Naganuma Makoto、Kinashi Tatsuo
    • Journal Title

      Frontiers in Immunology

      Volume: 14 Pages: 1234747-1234747

    • DOI

      10.3389/fimmu.2023.1234747

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Intravenous injection of tumor extracellular vesicles suppresses tumor growth by reducing the regulatory T cell phenotype2023

    • Author(s)
      Kobayashi Sanshiro、Kondo Naoyuki、Tomiyama Takashi、Nakamura Naohiro、Masuda Masataka、Matsumoto Yasushi、Honzawa Yusuke、Tahara Tomomitsu、Ikeura Tsukasa、Fukui Toshiro、Okazaki Kazuichi、Naganuma Makoto
    • Journal Title

      Cancer Immunology, Immunotherapy

      Volume: 72 Issue: 11 Pages: 3651-3664

    • DOI

      10.1007/s00262-023-03517-0

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed
  • [Journal Article] LFA1 Activation: Insights from a Single-Molecule Approach2022

    • Author(s)
      Kondo Naoyuki、Ueda Yoshihiro、Kinashi Tatsuo
    • Journal Title

      Cells

      Volume: 11 Issue: 11 Pages: 1751-1751

    • DOI

      10.3390/cells11111751

    • Related Report
      2022 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Kindlin-3はインテグリンLFA-1のサブユニット間の 会合を阻害してRap1およびtalin1による 正のフィードバックを活性化させる2022

    • Author(s)
      近藤直幸、木梨達雄
    • Journal Title

      シグナリングに載った日本人研究者2021

      Volume: 2022 Pages: 10-11

    • Related Report
      2022 Research-status Report
    • Open Access
  • [Journal Article] Kindlin-3 disrupts an intersubunit association in the integrin LFA1 to trigger positive feedback activation by Rap1 and talin1,2021

    • Author(s)
      Kondo N, Ueda Y, Kinashi T.
    • Journal Title

      Sci Signal.

      Volume: Vol 14, Issue 686. Issue: 686

    • DOI

      10.1126/scisignal.abf2184

    • Related Report
      2021 Research-status Report
    • Peer Reviewed
  • [Journal Article] Combination therapy with lenvatinib and radiation significantly inhibits thyroid cancer growth by uptake of tyrosine kinase inhibitor2021

    • Author(s)
      Suzuki Kensuke、Iwai Hiroshi、Utsunomiya Keita、Kono Yumiko、Kobayashi Yoshiki、Van Bui Dan、Sawada Shunsuke、Yun Yasutaka、Mitani Akitoshi、Kondo Naoyuki、Katano Tayo、Tanigawa Noboru、Akama Tomoya、Kanda Akira
    • Journal Title

      Experimental Cell Research

      Volume: 398 Issue: 1 Pages: 112390-112390

    • DOI

      10.1016/j.yexcr.2020.112390

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] MST1/2 Balance Immune Activation and Tolerance by Orchestrating Adhesion, Transcription, and Organelle Dynamics in Lymphocytes2020

    • Author(s)
      Ueda Yoshihiro、Kondo Naoyuki、Kinashi Tatsuo
    • Journal Title

      Frontiers in Immunology

      Volume: 11 Pages: 733-733

    • DOI

      10.3389/fimmu.2020.00733

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] オートファゴソーム含有因子LC3によるリンパ球細胞接着面へのインテグリンLFA1輸送の制御2023

    • Author(s)
      近藤直幸, 清末優子, 木梨達雄
    • Organizer
      第96回日本生化学会大会
    • Related Report
      2023 Annual Research Report
  • [Presentation] Cytoskeleton-Organelle Interaction in Cells Expressing INF2 Variants that Cause Glomerulopathy and Peripheral Neuropathy2023

    • Author(s)
      トランチュイフォンクィン, 近藤直幸, 塚口裕康
    • Organizer
      第96回日本生化学会大会
    • Related Report
      2023 Annual Research Report
  • [Presentation] Distinct bidirectional regulation of integrins by Rap1, talin1 and kindlin-3 in T cells under shear flow2023

    • Author(s)
      Kamioka Y., Ueda Y., Kondo N., and Kinashi T.
    • Organizer
      第52回日本免疫学会学術集会
    • Related Report
      2023 Annual Research Report
  • [Presentation] Rap1-Talin1 axis facilitates front-back cell polarity independent of talin 1 binding to integrins in lymphocytes2023

    • Author(s)
      Ueda Y., Higasa K., Kamioka Y., Kondo N., Horitani S., Ikeda Y., Bergmeier W., Fukui Y., and Kinashi T.
    • Organizer
      第52回日本免疫学会学術集会
    • Related Report
      2023 Annual Research Report
  • [Presentation] Rap1-GAPs Rasa3 and Sipa1 are required for pulmonary transit and egress from the lymph nodes in T cells2023

    • Author(s)
      Horitani S., Ueda Y., Kamioka Y., Kondo N., Naganuma M., and Kinashi T.
    • Organizer
      第52回日本免疫学会学術集会
    • Related Report
      2023 Annual Research Report
  • [Presentation] Single-molecule dissection of leukocyte integrin LFA1 activation mechanism2023

    • Author(s)
      Kondo, N., Ueda, Y., and Kinashi, T.
    • Organizer
      Fibronectin, Integrins and the Extracellular Matrix, Gordon Research Conference
    • Related Report
      2022 Research-status Report
    • Int'l Joint Research
  • [Presentation] Subsecond Rap1 activation by outside-in signaling of LFA1/ICAM1 interactions strengthens L-selectin mediated rolling of T cells2022

    • Author(s)
      Kamioka Y., Ueda Y., Kondo N., Ikeda Y., Kinashi T.
    • Organizer
      第51回日本免疫学会学術集会
    • Related Report
      2022 Research-status Report
  • [Presentation] Rap1 facilitates cell polarization via RhoA signaling in T cells2022

    • Author(s)
      Ueda Y., Higasa K., Kamioka Y., Kondo N., Horitani S., Ikeda Y., Fukuhara T., Fukuhara T., Fukui Y. and Kinashi T
    • Organizer
      第51回日本免疫学会学術集会
    • Related Report
      2022 Research-status Report
  • [Presentation] Distinct binding properties of integrin adaptors talin1 and kindlin-3 to LFA1 and α4 integrins modulated adhesive responses in static and shear-flow conditions2022

    • Author(s)
      Kondo N., Kamioka Y., Ikeda Y., Ueda Y., Kinashi T.
    • Organizer
      第51回日本免疫学会学術集会
    • Related Report
      2022 Research-status Report
  • [Presentation] The critical role of Rap1GAPs in T cell recirculation and egress from lymph node2022

    • Author(s)
      Horitani S., Ueda Y., Kamioka Y., Kondo N., Ikeda Y., Fukuhara T., Naganuma M. and Kinashi T.
    • Organizer
      第51回日本免疫学会学術集会
    • Related Report
      2022 Research-status Report
  • [Presentation] オートファジー関連経路のリンパ球細胞接着能への関与2022

    • Author(s)
      近藤直幸, 清末優子, 木梨達雄
    • Organizer
      第45回日本分子生物学会年会
    • Related Report
      2022 Research-status Report
  • [Presentation] Kindlin-3 breaks of integrin LFA-1 inhibitory clasp to promote positive feedback activation of LFA-12021

    • Author(s)
      Naoyuki Kondo, Yoshiro Ueda, Tatsuo Kinashi
    • Organizer
      第50回日本免疫学会学術集会
    • Related Report
      2021 Research-status Report
  • [Presentation] Rap1 facilitates T cell polarity via spatial regulation of MLC and ARAP12021

    • Author(s)
      Yoshiro Ueda, Koichiro Higasa, Yuji Kamioka, Naoyuki Kondo, Tatsuo Kinashi
    • Organizer
      第50回日本免疫学会学術集会
    • Related Report
      2021 Research-status Report
  • [Presentation] Differential requirement of Rap1 and integrin adaptors for distinct modalities of T cell adhesion under shear flow2021

    • Author(s)
      Yuji Kamioka, Yoshiro Ueda, Naoyuki Kondo, Tatsuo Kinashi
    • Organizer
      第50回日本免疫学会学術集会
    • Related Report
      2021 Research-status Report
  • [Presentation] 細胞内アダプタータンパク質の一分子動態計測によるインテグリンLFA-1活性化機構の解明2021

    • Author(s)
      近藤直幸, 植田祥啓, 木梨達雄
    • Organizer
      第94回日本生化学会大会
    • Related Report
      2021 Research-status Report
  • [Presentation] インテグリン活性化因子の局所的運動特性の違いによる免疫細胞移動メカニズムの解明2021

    • Author(s)
      近藤直幸, 植田祥啓, 南暁彦, 真上薫, 木梨達雄
    • Organizer
      関西医科大学第5回学術祭
    • Related Report
      2021 Research-status Report
  • [Presentation] 構造解析コンソーシアムの発展と活用による分子に基づいた分野横断型橋渡し研究への展開2021

    • Author(s)
      近藤直幸,片野泰代, 赤間智也, 池田幸樹, 鈴木健介, 富山尚, 寿野良二, 神田晃, 八木正夫, 岩井大
    • Organizer
      関西医科大学第5回学術祭
    • Related Report
      2021 Research-status Report
  • [Presentation] インテグリンによる細胞接着を介した免疫調節機構の解明と応用2021

    • Author(s)
      木梨達雄, 植田祥啓, 上岡裕治, 近藤直幸, 池田幸樹
    • Organizer
      私立大学研究ブランディング事業シンポジウム
    • Related Report
      2020 Research-status Report
  • [Presentation] Rap1/Talin-1/Kindlin-3を内包する新規ポジティブフィードバック回路によるインテグリン活性化の離散的制御2020

    • Author(s)
      近藤直幸, 植田祥啓, 木梨達雄
    • Organizer
      第43回日本分子生物学会年会
    • Related Report
      2020 Research-status Report
  • [Presentation] 「構造解析コンソーシアム」の確立による分子に基づいた橋渡し研究の推進2020

    • Author(s)
      近藤直幸, 片野泰代, 赤間智也, 寿野良二, 池田幸樹, 鈴木健介, 富山尚, 神田晃, 八木正夫, 岩井大
    • Organizer
      関西医科大学第4回学術祭
    • Related Report
      2020 Research-status Report
  • [Presentation] 病原性小胞の制御を目指したインテグリン含有小胞の制御機構と生理学的意義の解明2020

    • Author(s)
      近藤直幸
    • Organizer
      関西医科大学第4回学術祭
    • Related Report
      2020 Research-status Report

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Published: 2020-04-28   Modified: 2025-01-30  

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