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Development of a new therapeutic agent that inhibits the production of exosome-associated Shiga toxin 2

Research Project

Project/Area Number 18K07128
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 49050:Bacteriology-related
Research InstitutionDoshisha University

Principal Investigator

Takahashi Miho  同志社大学, 生命医科学部, 助教 (00446569)

Project Period (FY) 2018-04-01 – 2021-03-31
Project Status Completed (Fiscal Year 2020)
Budget Amount *help
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2020: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
Fiscal Year 2019: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Keywords志賀毒素 / エキソソーム(エクソソーム) / 小胞輸送 / プロテインキナーゼ / エキソソーム / ペプチドアレイ / エクソソーム / キナーゼ / 基質ペプチドアレイ / Shia toxin (Stx)
Outline of Final Research Achievements

After being incorporated into target cells, Shiga toxin 2 (Stx2) was actively released from the cells, and part of released Stx2a was associated with exosomes (refer to as exo-Stx2). To determine the intracellular molecules that regulate the production of exo-Stx2, we examined the effect of knockdown of Rabs (Rab11a, Rab11b, Rab27a, Rab27b, and Rab35) on the release of Stx2 in the culture medium. The results showed that the release of Stx2 was inhibited by Rab11b knockdown but not by the other Rabs knockdown, indicating that exo-Stx2 is released by Rab11b dependent machinery. By using a kinase substrate peptide array, we analyzed the hundreds of protein kinases activations in Stx treated cells, and found that the types of activated protein kinases were different between the case with Stx1 and Stx2 in the intracellular transport of Stx.

Academic Significance and Societal Importance of the Research Achievements

Stx2が細胞内に取り込まれた後、その一部がエキソソームに結合した状態(exo-Stx2)で細胞外へ放出されるが、このexo-Stx2をマウスに静脈投与した場合、遊離型Stx2に比べマウスに対する個体毒性が増強することがわかっている。従って、exo-Stx2がどのような分子機構で産生されているのかを明らかにし、さらにその産生を制御する分子を同定できれば、Stx2の強毒性に関わる分子を標的とした新しい腸管出血性大腸菌感染症治療薬が開発可能となることが期待される。

Report

(4 results)
  • 2020 Annual Research Report   Final Research Report ( PDF )
  • 2019 Research-status Report
  • 2018 Research-status Report
  • Research Products

    (4 results)

All 2021 2018

All Journal Article (3 results) (of which Peer Reviewed: 3 results,  Open Access: 3 results) Presentation (1 results) (of which Int'l Joint Research: 1 results)

  • [Journal Article] A nontoxigenic form of Shiga toxin 2 suppresses the production of amyloid b by altering the intracellular transport of amyloid precursor protein through its receptor-binding B-subunit2021

    • Author(s)
      Waka Sato, Miho Watanabe-Takahashi, Takashi Hamabata, Koichi Furukawa, Satoru Funamoto, Kiyotaka Nishikawa
    • Journal Title

      Biochemical and Biophysical Research Communications

      Volume: 557 Pages: 247-253

    • DOI

      10.1016/j.bbrc.2021.04.015

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Identification of a peptide motif that potently inhibits two functionally distinct subunits of Shiga toxin2021

    • Author(s)
      Miho Watanabe-Takahashi, Masakazu Tamada, Miki Senda, Masahiro Hibino, Eiko Shimizu, Akiko Okuta, Atsuo Miyazawa, Toshiya Senda, Kiyotaka Nishikawa
    • Journal Title

      Communications biology

      Volume: 538 Issue: 1 Pages: 1-7

    • DOI

      10.1038/s42003-021-02068-3

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Exosome-associated Shiga toxin 2 is released from cells and causes severe toxicity in mice2018

    • Author(s)
      Watanabe-Takahashi, M., Yamasaki, S., Murata, M., Kano, F., Motoyama, J., Yamate, J., Omi, J., Sato, W., Ukai, H., Shimasaki, K., Ikegawa, M., Tamura-Nakano, M., Yanoshita, R., Nishino, Y., Miyazawa, A., Natori, Y., Toyama-Sorimachi, N., Nishikawa, N.
    • Journal Title

      Sci. Rep.

      Volume: 8 Issue: 1 Pages: 10776-10776

    • DOI

      10.1038/s41598-018-29128-9

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] Exosome-associated Shiga toxin 2 is released from cells and causes severe toxicity in mice.2018

    • Author(s)
      Miho Watanabe-Takahashi, Jun Motoyama, Jyoji Yamate, Shinji Yamasaki and Kiyotaka Nishikawa
    • Organizer
      VTEC2018
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research

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Published: 2018-04-23   Modified: 2022-01-27  

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