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Novel reactive persulfide-producing system in bacteria and its involvement in bacterial pathogenicity

Research Project

Project/Area Number 18K07099
Research Category

Grant-in-Aid for Scientific Research (C)

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

Principal Investigator

藤井 重元  東北大学, 医学系研究科, 大学院非常勤講師 (00325333)

Co-Investigator(Kenkyū-buntansha) 井田 智章  東北大学, 医学系研究科, 助教 (70570406)
高田 剛  東北大学, 医学系研究科, 学術研究員 (20733257)
Project Period (FY) 2018-04-01 – 2020-03-31
Project Status Discontinued (Fiscal Year 2019)
Budget Amount *help
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2020: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2018: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
Keywords活性イオウ分子 / 硫化水素 / 細菌感染 / オートファジー / 感染防御 / 細菌 / 活性イオウ分子種 / システインパースルフィド / タンパク質ポリサルファー化
Outline of Annual Research Achievements

本研究では、細菌の活性イオウ代謝系に焦点をあて、活性イオウ分子種のオートファジー抑制作用ならびに細胞内殺菌回避を介する病原性発現機構を明らかにした。具体的には、細菌が産生する活性イオウ産生機構と活性イオウ分子によるオートファジー制御を解析した。我々が作製したネズミチフス菌の主要な硫化水素産生酵素であるチオ硫酸還元酵素および亜硫酸還元酵素の欠損株の活性イオウ分子の産生レベルを解析した結果、野生型と比べて各欠損株において、システインパースルフィド、グルタチオンパースルフィドをはじめとする各種活性イオウ分子産生量の有意な減少を認めた。さらにマウスマクロファージ細胞にネズミチフス菌の野生型および活性パースルフィド生成変異株を感染させ、オートファジー誘導と細胞内増殖を解析した結果、細菌由来の活性イオウ分子がオートファジーを抑制することが分かった。これらの結果から、ネズミチフス菌が産生する活性イオウ分子は、オートファジー誘導制御に重要な役割を果たしていることが示された。また、研究を進める中で得られた新知見として、グルタチオンポリスルフィドなどの酸化型イオウ分子が、マクロファージなどの食細胞が発現する誘導型一酸化窒素合成酵素(inducible isoform of nitric oxide synthase, iNOS)によりNADPH依存的な還元酸化反応により活性化され還元型活性パースルフィドが産生されることが分かってきた。また、iNOSの本来の代謝産物であるNOが、この活性パースルフィドと反応し、ニトロソパースルフィドなど、さらに化学的反応性の高まった活性代謝物が産生されことが明らかとなった。このことは、サルモネラなどの細胞内寄生において、菌体側から産生されるイオウ代謝物を、宿主のiNOS などが再活性化することで、病原菌の毒性制御と宿主の感染防御に寄与していることを示唆している。

Report

(2 results)
  • 2019 Annual Research Report
  • 2018 Research-status Report
  • Research Products

    (42 results)

All 2020 2019 2018 Other

All Int'l Joint Research (4 results) Journal Article (17 results) (of which Int'l Joint Research: 13 results,  Peer Reviewed: 17 results,  Open Access: 16 results) Presentation (16 results) (of which Int'l Joint Research: 2 results,  Invited: 1 results) Book (3 results) Remarks (2 results)

  • [Int'l Joint Research] National Institute of Oncology(ハンガリー)

    • Related Report
      2019 Annual Research Report
  • [Int'l Joint Research] Karolinska Institutet(スウェーデン)

    • Related Report
      2019 Annual Research Report
  • [Int'l Joint Research] Sonoma State University/Massachusetts General Hospital/Washington State University(米国)

    • Related Report
      2019 Annual Research Report
  • [Int'l Joint Research] Southampton General Hospital/University of Birmingham/The Rayne Institute(英国)

    • Related Report
      2019 Annual Research Report
  • [Journal Article] Control of Protein Function Through Oxidation and Reduction of Persulfidated States2020

    • Author(s)
      E Doka, T Ida, M Dagnell, Y Abiko, N C Luong, N Balog, T Takata, B Espinosa, A Nishimura, Q Cheng, Y Funato, H Miki, J M Fukuto, J R Prigge, E E Schmidt, E S J Arner, Y Kumagai, T Akaike, P Nagy
    • Journal Title

      Sci Adv

      Volume: 6 Issue: 1 Pages: 8358-8358

    • DOI

      10.1126/sciadv.aax8358

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] The active-site cysteine residue of Ca2+/calmodulin-dependent protein kinase I is protected from irreversible modification via generation of polysulfidation2019

    • Author(s)
      Takata Tsuyoshi、Tsukuda Ayaka、Tsuchiya Yukihiro、Akaike Takaaki、Watanabe Yasuo
    • Journal Title

      Nitric Oxide

      Volume: 86 Pages: 68-75

    • DOI

      10.1016/j.niox.2019.02.008

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Environmental Electrophile-Mediated Toxicity in Mice Lacking Nrf2, CSE, or Both2019

    • Author(s)
      Akiyama Masahiro、Unoki Takamitsu、Shinkai Yasuhiro、Ishii Isao、Ida Tomoaki、Akaike Takaaki、Yamamoto Masayuki、Kumagai Yoshito
    • Journal Title

      Environmental Health Perspectives

      Volume: 127 Issue: 6 Pages: 067002-067002

    • DOI

      10.1289/ehp4949

    • NAID

      120007133174

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Oxidation of PKGIα mediates an endogenous adaptation to pulmonary hypertension2019

    • Author(s)
      Rudyk Olena、Rowan Alice、Prysyazhna Oleksandra、Krasemann Susanne、Hartmann Kristin、Zhang Min、Shah Ajay M.、Ruppert Clemens、Weiss Astrid、Schermuly Ralph T.、Ida Tomoaki、Akaike Takaaki、Zhao Lan、Eaton Philip
    • Journal Title

      Proceedings of the National Academy of Sciences

      Volume: 116 Issue: 26 Pages: 13016-13025

    • DOI

      10.1073/pnas.1904064116

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Data‐Driven Identification of Hydrogen Sulfide Scavengers2019

    • Author(s)
      Yang Chun‐tao、Wang Yingying、Marutani Eizo、Ida Tomoaki、Ni Xiang、Xu Shi、Chen Wei、Zhang Hui、Akaike Takaaki、Ichinose Fumito、Xian Ming
    • Journal Title

      Angewandte Chemie International Edition

      Volume: 58 Issue: 32 Pages: 10898-10902

    • DOI

      10.1002/anie.201905580

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Mitochondrial cysteinyl-tRNA synthetase is expressed via alternative transcriptional initiation regulated by energy metabolism in yeast cells2019

    • Author(s)
      Nishimura Akira、Nasuno Ryo、Yoshikawa Yuki、Jung Minkyung、Ida Tomoaki、Matsunaga Tetsuro、Morita Masanobu、Takagi Hiroshi、Motohashi Hozumi、Akaike Takaaki
    • Journal Title

      Journal of Biological Chemistry

      Volume: 294 Issue: 37 Pages: 13781-13788

    • DOI

      10.1074/jbc.ra119.009203

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Long-lasting blood pressure lowering effects of nitrite are NO-independent and mediated by hydrogen peroxide, persulfides, and oxidation of protein kinase G1α redox signalling2019

    • Author(s)
      Feelisch Martin、Akaike Takaaki、Griffiths Kayleigh、Ida Tomoaki、Prysyazhna Oleksandra、Goodwin Joanna J、Gollop Nicholas D、Fernandez Bernadette O、Minnion Magdalena、Cortese-Krott Miriam M、Borgognone Alessandra、Hayes Rosie M、Eaton Philip、Frenneaux Michael P、Madhani Melanie
    • Journal Title

      Cardiovascular Research

      Volume: 116 Issue: 1 Pages: 51-62

    • DOI

      10.1093/cvr/cvz202

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] The Uptake and Release of Polysulfur Cysteine Species by Cells: Physiological and Toxicological Implications.2019

    • Author(s)
      Lin J, Akiyama M, Bica I, Long FT, Henderson CF, Goddu RN, Suarez V, Baker B, Ida T, Shinkai Y, Nagy P, Akaike T, Fukuto JM, Kumagai Y.
    • Journal Title

      Chem Res Toxicol

      Volume: 32 Issue: 3 Pages: 447-455

    • DOI

      10.1021/acs.chemrestox.8b00340

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Polysulfide stabilization by tyrosine and hydroxyphenyl-containing derivatives that is important for a reactive sulfur metabolomics analysis.2019

    • Author(s)
      Hamid HA, Tanaka A, Ida T, Nishimura A, Matsunaga T, Fujii S, Morita M, Sawa T, Fukuto JM, Nagy P, Tsutsumi R, Motohashi H, Ihara H, Akaike T.
    • Journal Title

      Redox Biol

      Volume: 21 Pages: 101096-101096

    • DOI

      10.1016/j.redox.2019.101096

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Production of 8-nitro-cGMP in osteocytic cells and its upregulation by parathyroid hormone and prostaglandin E2.2019

    • Author(s)
      Nagayama K, Miyamoto Y, Kaneko K, Yoshimura K, Sasa K, Akaike T, Fujii S, Izumida E, Uyama R, Chikazu D, Maki K, Kamijo R.
    • Journal Title

      In Vitro Cell Dev Biol Anim

      Volume: 55 Issue: 1 Pages: 45-51

    • DOI

      10.1007/s11626-018-0304-0

    • Related Report
      2018 Research-status Report
    • Peer Reviewed
  • [Journal Article] Persulfide synthases that are functionally coupled with translation mediate sulfur respiration in mammalian cells.2019

    • Author(s)
      Fujii S, Sawa T, Motohashi H, Akaike T.
    • Journal Title

      Br J Pharmacol

      Volume: 176 Issue: 4 Pages: 607-615

    • DOI

      10.1111/bph.14356

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Speciation of reactive sulfur species and their reactions with alkylating agents: do we have any clue about what is present inside the cell?2018

    • Author(s)
      Bogdandi Virag、Ida Tomoaki、Sutton Thomas R、Bianco Christopher、Ditroi Tamas、Koster Grielof、Henthorn Hillary A、Minnion Magda、Toscano John P、van der Vliet Albert、Pluth Michael D、Feelisch Martin、Fukuto Jon M、Akaike Takaaki、Nagy Peter
    • Journal Title

      British Journal of Pharmacology

      Volume: 176 Issue: 4 Pages: 646-670

    • DOI

      10.1111/bph.14394

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] The reaction of hydrogen sulfide with disulfides: formation of a stable trisulfide and implications for biological systems2018

    • Author(s)
      Bianco Christopher L、Akaike Takaaki、Ida Tomoaki、Nagy Peter、Bogdandi Virag、Toscano John P、Kumagai Yoshito、Henderson Catherine F、Goddu Robert N、Lin Joseph、Fukuto Jon M
    • Journal Title

      British Journal of Pharmacology

      Volume: 176 Issue: 4 Pages: 671-683

    • DOI

      10.1111/bph.14372

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Important role of endothelial caveolin-1 in the protective role of endothelium-dependent hyperpolarization against nitric oxide-mediated nitrative stress in microcirculation in mice2018

    • Author(s)
      Saito H, Godo S, Sato S, Ito A, Ikumi Y, Tanaka S, Ida T, Fujii S, Akaike T, Shimokawa H.
    • Journal Title

      Journal of Cardiovascular Pharmacology

      Volume: 71 Issue: 2 Pages: 113-126

    • DOI

      10.1097/fjc.0000000000000552

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Reactive Persulfides from Salmonella Typhimurium Downregulate Autophagy-Mediated Innate Immunity in Macrophages by Inhibiting Electrophilic Signaling2018

    • Author(s)
      Khan Shahzada、Fujii Shigemoto、Matsunaga Tetsuro、Nishimura Akira、Ono Katsuhiko、Ida Tomoaki、Ahmed Khandaker Ahtesham、Okamoto Tatsuya、Tsutsuki Hiroyasu、Sawa Tomohiro、Akaike Takaaki
    • Journal Title

      Cell Chemical Biology

      Volume: 25 Issue: 11 Pages: 1403-1413

    • DOI

      10.1016/j.chembiol.2018.08.007

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Biological hydropersulfides and related polysulfides - a new concept and perspective in redox biology2018

    • Author(s)
      Fukuto Jon M.、Ignarro Louis J.、Nagy Peter、Wink David A.、Kevil Christopher G.、Feelisch Martin、Cortese-Krott Miriam M.、Bianco Christopher L.、Kumagai Yoshito、Hobbs Adrian J.、Lin Joseph、Ida Tomoaki、Akaike Takaaki
    • Journal Title

      FEBS Letters

      Volume: 592 Issue: 12 Pages: 2140-2152

    • DOI

      10.1002/1873-3468.13090

    • NAID

      120007133961

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Cysteine perthiosulfenic acid (Cys-SSOH): A novel intermediate in thiol-based redox signaling?2018

    • Author(s)
      Heppner DE, Hristova M, Ida T, Mijuskovic A, Dustin CM, Bogdandi V, Fukuto JM, Dick TP, Nagy P, Li J, Akaike T, van der Vliet A.
    • Journal Title

      Redox Biol.

      Volume: 14 Pages: 379-385

    • DOI

      10.1016/j.redox.2017.10.006

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] NADPH oxidaseによる新規活性硫黄代謝リモデリングと細菌感染防御機構2020

    • Author(s)
      井田智章、松永哲郎、守田匡伸、高田 剛、住本英樹、赤池孝章
    • Organizer
      第93回日本細菌学会総会
    • Related Report
      2019 Annual Research Report
  • [Presentation] 活性硫黄メタボロームの新展開2020

    • Author(s)
      井田智章、居原 秀、赤池孝章
    • Organizer
      第19回分子予防環境医学研究会大会
    • Related Report
      2019 Annual Research Report
    • Invited
  • [Presentation] NADPH酸化還元酵素による新規活性硫黄代謝機構の解明2020

    • Author(s)
      髙田剛、井田智章、松永哲郎、守田匡伸、土屋幸弘、渡邊泰男、住本英樹、赤池孝章
    • Organizer
      第19回分子予防環境医学研究会大会
    • Related Report
      2019 Annual Research Report
  • [Presentation] Translation-coupled protein polysulfidation, discovery of a novel cysteine persulfide synthase2019

    • Author(s)
      Tomoaki Ida, Masanobu Morita, Akira Nishimura, Tetsuro Matsunaga, Hideshi Ihara, Tomohiro Sawa, Hozumi Motohashi, Takaaki. Akaike
    • Organizer
      The 9th Biennial Meeting of SFRR Asia (SFRR-Asia 2019)
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 活性イオウ安定化と高精度イオウ代謝解析法の確立2019

    • Author(s)
      井田智章、松永哲郎、西村 明、守田匡伸、居原 秀、澤 智裕、本橋ほづみ、赤池孝章
    • Organizer
      第92回日本生化学会大会
    • Related Report
      2019 Annual Research Report
  • [Presentation] カルモデュリンキナーゼ群の活性イオウ分子応答性の差異2019

    • Author(s)
      髙田剛、土屋幸弘、赤池孝章、渡邊泰男
    • Organizer
      第92回日本生化学会大会
    • Related Report
      2019 Annual Research Report
  • [Presentation] カルモデュリンキナーゼIのポリスルフィド化とその意義2019

    • Author(s)
      髙田剛、佃彩華、土屋幸弘、赤池孝章、渡邊泰男
    • Organizer
      第19回日本NO学会学術集会
    • Related Report
      2019 Annual Research Report
  • [Presentation] チロシン・ヒドロキシフェニル基によるポリスルフィドの安定化2019

    • Author(s)
      井田 智章,松永 哲郎,西村 明,守田 匡伸,居原 秀,澤 智裕,本橋ほづみ,赤池 孝章
    • Organizer
      第18回 分子予防環境医学研究会大会(名古屋)
    • Related Report
      2018 Research-status Report
  • [Presentation] Translation-coupled protein polysulfidation, a unique biosynthesis pathway of cysteine persulfide2018

    • Author(s)
      Tomoaki Ida, Akira Nishimura, Masanobu Morita, Hideshi Ihara, Tomohiro Sawa, Shigemoto Fujii, Hozumi Motohashi, Takaaki Akaike
    • Organizer
      10th International Conference on the Biology, Chemistry and Therapeutic Applications of Nitric Oxide
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Presentation] システイニルtRNA合成酵素のパースルフィド合成制御機構2018

    • Author(s)
      井田 智章, 西村 明, 守田 匡伸, 松永 哲郎, 澤 智裕, 居原 秀, 藤井 重元, 本橋 ほづみ, 赤池 孝章
    • Organizer
      第91回 日本生化学会大会(京都)
    • Related Report
      2018 Research-status Report
  • [Presentation] システイニルtRNA合成酵素によるパースルフィド合成制御機構の解明2018

    • Author(s)
      井田 智章,西村 明,守田 匡伸,松永 哲郎,澤 智裕, 居原 秀,藤井 重元,本橋ほづみ,赤池 孝章
    • Organizer
      第71回 日本酸化ストレス学会・日本NO学会合同学術集会(京都)
    • Related Report
      2018 Research-status Report
  • [Presentation] ニトロソグルタチオン代謝酵素アルコールデヒドロゲナーゼ5のタンパク質ポリスルフィド化による制御機構2018

    • Author(s)
      藤井 重元,笠松真吾,Md. Morshedul Alam,井田 智章,守田 匡伸, 居原 秀,西村 明,松永 哲郎,本橋ほづみ,赤池 孝章
    • Organizer
      第71回日本酸化ストレス学会・日本NO学会合同学術集会(京都)
    • Related Report
      2018 Research-status Report
  • [Presentation] 種横断的システインパースルフィド合成酵素の発見とその生体防御機能の解明2018

    • Author(s)
      井田 智章,守田 匡伸,松永 哲郎,西村 明,居原 秀,澤 智裕, 藤井 重元 ,本橋ほづみ,赤池 孝章
    • Organizer
      第72回 日本細菌学会東北支部総会(仙台)
    • Related Report
      2018 Research-status Report
  • [Presentation] 種横断的新しいシステインパースルフィド合成酵素の発見2018

    • Author(s)
      井田 智章,守田 匡伸,松永 哲郎,西村 明,居原 秀,澤 智裕, 藤井 重元 ,本橋ほづみ,赤池 孝章
    • Organizer
      第29回 日本生体防御学会学術集会(京都)
    • Related Report
      2018 Research-status Report
  • [Presentation] 親電子解毒代謝系システインパースルフィドの新しい合成酵素の発見2018

    • Author(s)
      井田 智章,守田 匡伸,西村 明,松永 哲郎,居原 秀,澤 智裕, 藤井 重元,熊谷 嘉人,本橋ほづみ,赤池 孝章
    • Organizer
      第45回 日本毒性学会学術年会
    • Related Report
      2018 Research-status Report
  • [Presentation] システイニルtRNA合成酵素によるパースルフィド合成制御機構の解明2018

    • Author(s)
      井田智章,西村 明,守田匡伸,松永哲郎,澤 智裕, 居原 秀,藤井重元,本橋ほづみ,赤池孝章
    • Organizer
      平成30年度 生理学研究所研究会(岡崎)
    • Related Report
      2018 Research-status Report
  • [Book] 硫黄呼吸は幹細胞のエネルギー代謝を担っているか?2019

    • Author(s)
      高田剛、松永哲郎、赤池孝章
    • Total Pages
      120
    • Publisher
      再生医療
    • ISBN
      9784779223358
    • Related Report
      2019 Annual Research Report
  • [Book] ポリスルフィド化2018

    • Author(s)
      西村 明、井田智章、赤池孝章
    • Total Pages
      2
    • Publisher
      生体の科学
    • Related Report
      2018 Research-status Report
  • [Book] SH(ポリスルフィド)の酸化2018

    • Author(s)
      西村 明、井田智章、赤池孝章
    • Total Pages
      2
    • Publisher
      生体の科学
    • Related Report
      2018 Research-status Report
  • [Remarks] 東北大学大学院医学系研究科環境医学分野ホームページ

    • URL

      http://www.toxicosci.med.tohoku.ac.jp/index.html

    • Related Report
      2019 Annual Research Report
  • [Remarks] 東北大学大学院医学系研究科環境医学分野ホームページ

    • URL

      http://www.toxicosci.med.tohoku.ac.jp/

    • Related Report
      2018 Research-status Report

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Published: 2018-04-23   Modified: 2021-01-27  

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