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Molecular dissection of box jellyfish venom cytotoxicity highlights an effective venom antidote

Author

Listed:
  • Man-Tat Lau

    (The University of Sydney
    The University of Sydney)

  • John Manion

    (The University of Sydney)

  • Jamie B. Littleboy

    (The University of Sydney)

  • Lisa Oyston

    (The University of Sydney)

  • Thang M. Khuong

    (The University of Sydney)

  • Qiao-Ping Wang

    (The University of Sydney
    Sun Yat-sen University)

  • David T. Nguyen

    (Garvan Institute of Medical Research)

  • Daniel Hesselson

    (Garvan Institute of Medical Research
    UNSW Sydney)

  • Jamie E. Seymour

    (James Cook University)

  • G. Gregory Neely

    (The University of Sydney
    The University of Sydney)

Abstract

The box jellyfish Chironex fleckeri is extremely venomous, and envenoming causes tissue necrosis, extreme pain and death within minutes after severe exposure. Despite rapid and potent venom action, basic mechanistic insight is lacking. Here we perform molecular dissection of a jellyfish venom-induced cell death pathway by screening for host components required for venom exposure-induced cell death using genome-scale lenti-CRISPR mutagenesis. We identify the peripheral membrane protein ATP2B1, a calcium transporting ATPase, as one host factor required for venom cytotoxicity. Targeting ATP2B1 prevents venom action and confers long lasting protection. Informatics analysis of host genes required for venom cytotoxicity reveal pathways not previously implicated in cell death. We also discover a venom antidote that functions up to 15 minutes after exposure and suppresses tissue necrosis and pain in mice. These results highlight the power of whole genome CRISPR screening to investigate venom mechanisms of action and to rapidly identify new medicines.

Suggested Citation

  • Man-Tat Lau & John Manion & Jamie B. Littleboy & Lisa Oyston & Thang M. Khuong & Qiao-Ping Wang & David T. Nguyen & Daniel Hesselson & Jamie E. Seymour & G. Gregory Neely, 2019. "Molecular dissection of box jellyfish venom cytotoxicity highlights an effective venom antidote," Nature Communications, Nature, vol. 10(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-09681-1
    DOI: 10.1038/s41467-019-09681-1
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    Cited by:

    1. Sina Jami & Jennifer R. Deuis & Tabea Klasfauseweh & Xiaoyang Cheng & Sergey Kurdyukov & Felicity Chung & Andrei L. Okorokov & Shengnan Li & Jiangtao Zhang & Ben Cristofori-Armstrong & Mathilde R. Isr, 2023. "Pain-causing stinging nettle toxins target TMEM233 to modulate NaV1.7 function," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    2. Bei Wang & Arabella H. Wan & Yu Xu & Ruo-Xin Zhang & Ben-Chi Zhao & Xin-Yuan Zhao & Yan-Chuan Shi & Xiaolei Zhang & Yongbo Xue & Yong Luo & Yinyue Deng & G. Gregory Neely & Guohui Wan & Qiao-Ping Wang, 2023. "Identification of indocyanine green as a STT3B inhibitor against mushroom α-amanitin cytotoxicity," Nature Communications, Nature, vol. 14(1), pages 1-15, December.

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