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Identification of indocyanine green as a STT3B inhibitor against mushroom α-amanitin cytotoxicity

Author

Listed:
  • Bei Wang

    (Shenzhen Campus of Sun Yat-sen University)

  • Arabella H. Wan

    (Sun Yat-sen University)

  • Yu Xu

    (Shenzhen Campus of Sun Yat-sen University)

  • Ruo-Xin Zhang

    (Shenzhen Campus of Sun Yat-sen University)

  • Ben-Chi Zhao

    (Shenzhen Campus of Sun Yat-sen University)

  • Xin-Yuan Zhao

    (Shenzhen Campus of Sun Yat-sen University)

  • Yan-Chuan Shi

    (Garvan Institute of Medical Research)

  • Xiaolei Zhang

    (Sun Yat-sen University)

  • Yongbo Xue

    (Shenzhen Campus of Sun Yat-sen University)

  • Yong Luo

    (Shenzhen Campus of Sun Yat-sen University)

  • Yinyue Deng

    (Shenzhen Campus of Sun Yat-sen University)

  • G. Gregory Neely

    (The University of Sydney)

  • Guohui Wan

    (Sun Yat-sen University)

  • Qiao-Ping Wang

    (Shenzhen Campus of Sun Yat-sen University)

Abstract

The “death cap”, Amanita phalloides, is the world’s most poisonous mushroom, responsible for 90% of mushroom-related fatalities. The most fatal component of the death cap is α-amanitin. Despite its lethal effect, the exact mechanisms of how α-amanitin poisons humans remain unclear, leading to no specific antidote available for treatment. Here we show that STT3B is required for α-amanitin toxicity and its inhibitor, indocyanine green (ICG), can be used as a specific antidote. By combining a genome-wide CRISPR screen with an in silico drug screening and in vivo functional validation, we discover that N-glycan biosynthesis pathway and its key component, STT3B, play a crucial role in α-amanitin toxicity and that ICG is a STT3B inhibitor. Furthermore, we demonstrate that ICG is effective in blocking the toxic effect of α-amanitin in cells, liver organoids, and male mice, resulting in an overall increase in animal survival. Together, by combining a genome-wide CRISPR screen for α-amanitin toxicity with an in silico drug screen and functional validation in vivo, our study highlights ICG as a STT3B inhibitor against the mushroom toxin.

Suggested Citation

  • 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.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-37714-3
    DOI: 10.1038/s41467-023-37714-3
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    References listed on IDEAS

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    1. 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.
    2. Johannes Stadlmann & Jasmin Taubenschmid & Daniel Wenzel & Anna Gattinger & Gerhard Dürnberger & Frederico Dusberger & Ulrich Elling & Lukas Mach & Karl Mechtler & Josef M. Penninger, 2017. "Comparative glycoproteomics of stem cells identifies new players in ricin toxicity," Nature, Nature, vol. 549(7673), pages 538-542, September.
    3. Lai Wei & Derek Lee & Cheuk-Ting Law & Misty Shuo Zhang & Jialing Shen & Don Wai-Ching Chin & Allen Zhang & Felice Ho-Ching Tsang & Ceci Lok-Sze Wong & Irene Oi-Lin Ng & Carmen Chak-Lui Wong & Chun-Mi, 2019. "Genome-wide CRISPR/Cas9 library screening identified PHGDH as a critical driver for Sorafenib resistance in HCC," Nature Communications, Nature, vol. 10(1), pages 1-13, December.
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