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Dissemination of pathogenic bacteria is reinforced by a MARTX toxin effector duet

Author

Listed:
  • Sanghyeon Choi

    (Korea Advanced Institute of Science and Technology (KAIST)
    Korea Research Institute of Bioscience and Biotechnology (KRIBB))

  • Youngjin Lee

    (Korea Research Institute of Bioscience and Biotechnology (KRIBB))

  • Shinhye Park

    (Korea Research Institute of Bioscience and Biotechnology (KRIBB)
    Chungnam National University)

  • Song Yee Jang

    (Korea Research Institute of Bioscience and Biotechnology (KRIBB)
    KRIBB)

  • Jongbin Park

    (Korea Research Institute of Bioscience and Biotechnology (KRIBB))

  • Do Won Oh

    (Korea Research Institute of Bioscience and Biotechnology (KRIBB)
    KAIST)

  • Su-Man Kim

    (Korea Research Institute of Bioscience and Biotechnology (KRIBB)
    Chonnam National University)

  • Tae-Hwan Kim

    (Korea Research Institute of Bioscience and Biotechnology (KRIBB)
    Chungnam National University)

  • Ga Seul Lee

    (KRIBB
    Chungbuk National University)

  • Changyi Cho

    (Ewha Womans University)

  • Byoung Sik Kim

    (Ewha Womans University)

  • Donghan Lee

    (Korea Basic Science Institute)

  • Eun-Hee Kim

    (Korea Basic Science Institute)

  • Hae-Kap Cheong

    (Korea Basic Science Institute)

  • Jeong Hee Moon

    (KRIBB)

  • Ji-Joon Song

    (Korea Advanced Institute of Science and Technology (KAIST))

  • Jungwon Hwang

    (Korea Research Institute of Bioscience and Biotechnology (KRIBB))

  • Myung Hee Kim

    (Korea Research Institute of Bioscience and Biotechnology (KRIBB))

Abstract

Multiple bacterial genera take advantage of the multifunctional autoprocessing repeats-in-toxin (MARTX) toxin to invade host cells. Secretion of the MARTX toxin by Vibrio vulnificus, a deadly opportunistic pathogen that causes primary septicemia, the precursor of sepsis, is a major driver of infection; however, the molecular mechanism via which the toxin contributes to septicemia remains unclear. Here, we report the crystal and cryo-electron microscopy (EM) structures of a toxin effector duet comprising the domain of unknown function in the first position (DUF1)/Rho inactivation domain (RID) complexed with human targets. These structures reveal how the duet is used by bacteria as a potent weapon. The data show that DUF1 acts as a RID-dependent transforming NADase domain (RDTND) that disrupts NAD+ homeostasis by hijacking calmodulin. The cryo-EM structure of the RDTND-RID duet complexed with calmodulin and Rac1, together with immunological analyses in vitro and in mice, provide mechanistic insight into how V. vulnificus uses the duet to suppress ROS generation by depleting NAD(P)+ and modifying Rac1 in a mutually-reinforcing manner that ultimately paralyzes first line immune responses, promotes dissemination of invaders, and induces sepsis. These data may allow development of tools or strategies to combat MARTX toxin-related human diseases.

Suggested Citation

  • Sanghyeon Choi & Youngjin Lee & Shinhye Park & Song Yee Jang & Jongbin Park & Do Won Oh & Su-Man Kim & Tae-Hwan Kim & Ga Seul Lee & Changyi Cho & Byoung Sik Kim & Donghan Lee & Eun-Hee Kim & Hae-Kap C, 2024. "Dissemination of pathogenic bacteria is reinforced by a MARTX toxin effector duet," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-50650-0
    DOI: 10.1038/s41467-024-50650-0
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    References listed on IDEAS

    as
    1. Shivani Agarwal & Hyunjin Kim & Robin B. Chan & Shivangi Agarwal & Rebecca Williamson & Wonhwa Cho & Gilbert Di Paolo & Karla J. F. Satchell, 2015. "Erratum: Autophagy and endosomal trafficking inhibition by Vibrio cholerae MARTX toxin phosphatidylinositol-3-phosphate-specific phospholipase A1 activity," Nature Communications, Nature, vol. 6(1), pages 1-1, December.
    2. A. Phillip West & Igor E. Brodsky & Christoph Rahner & Dong Kyun Woo & Hediye Erdjument-Bromage & Paul Tempst & Matthew C. Walsh & Yongwon Choi & Gerald S. Shadel & Sankar Ghosh, 2011. "TLR signalling augments macrophage bactericidal activity through mitochondrial ROS," Nature, Nature, vol. 472(7344), pages 476-480, April.
    3. Josh Abramson & Jonas Adler & Jack Dunger & Richard Evans & Tim Green & Alexander Pritzel & Olaf Ronneberger & Lindsay Willmore & Andrew J. Ballard & Joshua Bambrick & Sebastian W. Bodenstein & David , 2024. "Accurate structure prediction of biomolecular interactions with AlphaFold 3," Nature, Nature, vol. 630(8016), pages 493-500, June.
    4. Shivani Agarwal & Hyunjin Kim & Robin B. Chan & Shivangi Agarwal & Rebecca Williamson & Wonhwa Cho & Gilbert Di Paolo & Karla J. F. Satchell, 2015. "Autophagy and endosomal trafficking inhibition by Vibrio cholerae MARTX toxin phosphatidylinositol-3-phosphate-specific phospholipase A1 activity," Nature Communications, Nature, vol. 6(1), pages 1-12, December.
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