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Functional analysis of exosome siRNA in Cholix-induced hepatic cell death

Research Project

Project/Area Number 19K07534
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 49050:Bacteriology-related
Research InstitutionKyoto Pharmaceutical University (2021)
Chiba University (2019-2020)

Principal Investigator

Yahiro Kinnosuke  京都薬科大学, 薬学部, 教授 (80345024)

Project Period (FY) 2019-04-01 – 2022-03-31
Project Status Completed (Fiscal Year 2021)
Budget Amount *help
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
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細菌毒素 / ADP-リボシル化 / PHB / マイクロアレイ解析 / miRNA / エキソソーム / 細胞死 / ADP-リボシル化毒素 / マイクロアレイ / Cholix / マイクロRNA
Outline of Research at the Start

コレラ菌由来外毒素 Cholix toxin (Cholix) は、宿主細胞内に侵入後、eEF2 を ADP-リボシル化し、タンパク質合成阻害活性に起因するアポトーシスを引き起こす蛋白質毒素である。本研究は、ヒト由来不死化正常肝細胞を用い、細胞致死に至る過程で放出されるエキソソーム内の microRNA (miRNA) を解析し、新たな細胞死亢進因子、致死過程特異的なコミュニケーション因子の同定・機能解析を行うことを目的とする。

Outline of Final Research Achievements

Cholix cytotoxin (Cholix) was identified as a novel eukaryotic elongation factor 2 (eEF2) ADP-ribosyltransferase produced mainly in non-O1/non-O139 V. cholerae. The function and role of Cholix in infectious disease caused by V. cholerae remain unknown. we identified prohibitin (PHB) 1 and 2 as novel Cholix-interacting membrane proteins in immortalized human hepatocytes.Cholix-induced reactive oxygen species (ROS) production and accumulation of fragmented mitochondria were enhanced in PHB-knockdown cells.Our findings identify PHB as a new protein that interacts with Cholix and is involved in Cholix-induced mitochondrial dysfunction and cytoskeletal rearrangement by ROCK1 activation during apoptosis. In addition, we investigated the change of mRNA or miRNA by RNAseq or miRNA microarray analysis in Cholix-treated cells. We believed that these data are crucial informations to provide us novel cell damage or response pathways.

Academic Significance and Societal Importance of the Research Achievements

緑膿菌の産生するExoA とよく似た構造と活性を持つ Cholix は、肝障害を引き起こす毒素である。 今回、Cholix の新規宿主細胞由来結合蛋白質としてProhibitin1,2 (PHB) を同定した。Cholix の細胞死に PHB が関与している事が分かった。ヒト由来不死化正常肝臓細胞を用いて Cholix による細胞内の mRNA, miRNA の網羅的解析(RNAseq 解析、マイクロアレイ解析)を行った。この解析結果は、これまで未知であった ADP-リボシル化による細胞死において、新規の宿主障害機構を見い出す貴重な基礎データとなると確信している。

Report

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

    (20 results)

All 2021 2020 2019 Other

All Int'l Joint Research (3 results) Journal Article (9 results) (of which Int'l Joint Research: 7 results,  Peer Reviewed: 9 results,  Open Access: 9 results) Presentation (7 results) (of which Int'l Joint Research: 1 results,  Invited: 4 results) Remarks (1 results)

  • [Int'l Joint Research] Dr. Joel Moss/NIH(米国)

    • Related Report
      2021 Annual Research Report
  • [Int'l Joint Research] NIH/NHLBI(米国)

    • Related Report
      2020 Research-status Report
  • [Int'l Joint Research] Dr. Joel Moss/NIH(米国)

    • Related Report
      2019 Research-status Report
  • [Journal Article] A novel endoplasmic stress mediator, Kelch domain containing 7B (KLHDC7B), increased Harakiri (HRK) in the SubAB-induced apoptosis signaling pathway2021

    • Author(s)
      Yahiro Kinnosuke、Ogura Kohei、Tsutsuki Hiroyasu、Iyoda Sunao、Ohnishi Makoto、Moss Joel
    • Journal Title

      Cell Death Discovery

      Volume: 7 Issue: 1 Pages: 360-360

    • DOI

      10.1038/s41420-021-00753-0

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Preparation of Biodegradable PLGA-Nanoparticles Used for pH-Sensitive Intracellular Delivery of an Anti-inflammatory Bacterial Toxin to Macrophages2020

    • Author(s)
      Harada Ayaka、Tsutsuki Hiroyasu、Zhang Tianli、Lee Ruda、Yahiro Kinnosuke、Sawa Tomohiro、Niidome Takuro
    • Journal Title

      Chemical and Pharmaceutical Bulletin

      Volume: 68 Issue: 4 Pages: 363-368

    • DOI

      10.1248/cpb.c19-00917

    • NAID

      130007824942

    • ISSN
      0009-2363, 1347-5223
    • Year and Date
      2020-04-01
    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Cell death signaling pathway induced by Cholix toxin, a cytotoxin and eEF2 ADP-ribosyltransferase produced by Vibrio cholerae2020

    • Author(s)
      Ogura, K. Yahiro, K. Moss, J.
    • Journal Title

      Toxins

      Volume: 13 Issue: 1 Pages: 12-12

    • DOI

      10.3390/toxins13010012

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Host response to the Subtilase cytotoxin produced by locus of enterocyte effacement (LEE)-negative Shiga-toxigenic Escherichia coli (STEC)2020

    • Author(s)
      Tsutsuki, H. Ogura, K. Moss, J. Yahiro, K.
    • Journal Title

      Microbiology and Immunology.

      Volume: 64 Issue: 10 Pages: 657-665

    • DOI

      10.1111/1348-0421.12841

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Subtilase cytotoxin induces a novel form of Lipocalin 2, which promotes Shiga-toxigenic Escherichia coli survival.2020

    • Author(s)
      Yahiro, K., Ogura, K., Goto, Y., Iyoda, S., Kobayashi, T., Takeuchi, H., Ohnishi, M., Moss, J.
    • Journal Title

      Scientific Reports.

      Volume: 10 Issue: 1 Pages: 18943-18943

    • DOI

      10.1038/s41598-020-76027-z

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Involvement of protein disulfide isomerase in subtilase cytotoxin-induced cell death in HeLa cells2020

    • Author(s)
      Tsutsuki Hiroyasu、Zhang Tianli、Harada Ayaka、Rahman Azizur、Ono Katsuhiko、Yahiro Kinnosuke、Niidome Takuro、Sawa Tomohiro
    • Journal Title

      Biochemical and Biophysical Research Communications

      Volume: 525 Issue: 4 Pages: 1068-1073

    • DOI

      10.1016/j.bbrc.2020.03.008

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Cholix toxin, an eEF2 ADP-ribosyltransferase, interacts with Prohibitins and induces apoptosis with mitochondrial dysfunction in human hepatocytes.2019

    • Author(s)
      Yahiro K, Ogura K, Terasaki Y, Satoh M, Miyagi S, Terasaki M, Yamasaki E, Moss J.
    • Journal Title

      Cell Microbiol.

      Volume: 4 Issue: 8

    • DOI

      10.1111/cmi.13033

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Helicobacter pylori Vacuolating Cytotoxin A Causes Anorexia and Anxiety via Hypothalamic Urocortin 1 in Mice2019

    • Author(s)
      Suzuki H, Ataka K, Asakawa A, Cheng KC, Ushikai M, Iwai H, Yagi T, Arai T, Yahiro K, Yamamoto K, Yokoyama Y, Kojima M, Yada T, Hirayama T, Nakamura N, Inui A
    • Journal Title

      Sci Rep

      Volume: 9 Issue: 1 Pages: 6011-6011

    • DOI

      10.1038/s41598-019-42163-4

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] A CRISPR Screen Using Subtilase Cytotoxin Identifies SLC39A9 as a Glycan-Regulating Factor2019

    • Author(s)
      Yamaji Toshiyuki、Hanamatsu Hisatoshi、Sekizuka Tsuyoshi、Kuroda Makoto、Iwasaki Norimasa、Ohnishi Makoto、Furukawa Jun-ichi、Yahiro Kinnosuke、Hanada Kentaro
    • Journal Title

      iScience

      Volume: 15 Pages: 407-420

    • DOI

      10.1016/j.isci.2019.05.005

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] SubABにより誘導される新規Lipocalin-2 の制御と細胞致死機構2021

    • Author(s)
      八尋錦之助, 小倉康平, 後藤義幸, 伊豫田淳, 小林達也, 竹内裕紀, 大西真
    • Organizer
      第67回トキシンシンポジウム
    • Related Report
      2021 Annual Research Report
  • [Presentation] 腸管出血性大腸菌の産生する小胞体ストレス誘導毒素の宿主応答解析2021

    • Author(s)
      八尋 錦之助
    • Organizer
      学校法人 北里研究所 2020年度 第30回 学会賞受賞者特別講演会
    • Related Report
      2021 Annual Research Report
    • Invited
  • [Presentation] 腸管出血性大腸菌の産生する小胞体ストレス誘導毒素の宿主応答機能解析2021

    • Author(s)
      八尋錦之助
    • Organizer
      学校法人北里研究所第30回学会賞受賞者特別講演会
    • Related Report
      2020 Research-status Report
    • Invited
  • [Presentation] SubAB induces a novel form of Lipocalin 2, which involves in STEC survival2021

    • Author(s)
      八尋錦之助
    • Organizer
      第94回日本細菌学会総会
    • Related Report
      2020 Research-status Report
  • [Presentation] Cholix toxin, an eEF2 ADP-ribosyltransferase, induces cell death signaling pathway2020

    • Author(s)
      八尋錦之助
    • Organizer
      第93回日本生化学会大会
    • Related Report
      2020 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] 腸管出血性大腸菌の産生する小胞体ストレス誘導毒素の宿主受容体と宿主応答解析2020

    • Author(s)
      八尋錦之助
    • Organizer
      第31回生体防御学会学術総会(熊本)
    • Related Report
      2020 Research-status Report
    • Invited
  • [Presentation] ヒト肝臓細胞における新規Cholix結合膜蛋白質の同定と細胞致死機構の解明2020

    • Author(s)
      八尋 錦之助、小倉 康平、寺﨑 泰弘、宮城 聡、山崎栄樹
    • Organizer
      第93回日本細菌学会総会
    • Related Report
      2019 Research-status Report
  • [Remarks] 京都薬科大学 微生物感染制御学 研究業績

    • URL

      https://labo.kyoto-phu.ac.jp/bisei/publications.html

    • Related Report
      2021 Annual Research Report

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

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