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Artemisinin kills malaria parasites by damaging proteins and inhibiting the proteasome

Author

Listed:
  • Jessica L. Bridgford

    (The University of Melbourne)

  • Stanley C. Xie

    (The University of Melbourne)

  • Simon A. Cobbold

    (The University of Melbourne)

  • Charisse Flerida A. Pasaje

    (The University of Melbourne)

  • Susann Herrmann

    (The University of Melbourne)

  • Tuo Yang

    (The University of Melbourne)

  • David L. Gillett

    (The University of Melbourne)

  • Lawrence R. Dick

    (Takeda Pharmaceuticals International Co)

  • Stuart A. Ralph

    (The University of Melbourne)

  • Con Dogovski

    (The University of Melbourne)

  • Natalie J. Spillman

    (The University of Melbourne)

  • Leann Tilley

    (The University of Melbourne)

Abstract

Artemisinin and its derivatives (collectively referred to as ARTs) rapidly reduce the parasite burden in Plasmodium falciparum infections, and antimalarial control is highly dependent on ART combination therapies (ACTs). Decreased sensitivity to ARTs is emerging, making it critically important to understand the mechanism of action of ARTs. Here we demonstrate that dihydroartemisinin (DHA), the clinically relevant ART, kills parasites via a two-pronged mechanism, causing protein damage, and compromising parasite proteasome function. The consequent accumulation of proteasome substrates, i.e., unfolded/damaged and polyubiquitinated proteins, activates the ER stress response and underpins DHA-mediated killing. Specific inhibitors of the proteasome cause a similar build-up of polyubiquitinated proteins, leading to parasite killing. Blocking protein synthesis with a translation inhibitor or inhibiting the ubiquitin-activating enzyme, E1, reduces the level of damaged, polyubiquitinated proteins, alleviates the stress response, and dramatically antagonizes DHA activity.

Suggested Citation

  • Jessica L. Bridgford & Stanley C. Xie & Simon A. Cobbold & Charisse Flerida A. Pasaje & Susann Herrmann & Tuo Yang & David L. Gillett & Lawrence R. Dick & Stuart A. Ralph & Con Dogovski & Natalie J. S, 2018. "Artemisinin kills malaria parasites by damaging proteins and inhibiting the proteasome," Nature Communications, Nature, vol. 9(1), pages 1-9, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-06221-1
    DOI: 10.1038/s41467-018-06221-1
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    Cited by:

    1. Hui Min & Xiaoying Liang & Chengqi Wang & Junling Qin & Rachasak Boonhok & Azhar Muneer & Awtum M. Brashear & Xiaolian Li & Allen M. Minns & Swamy Rakesh Adapa & Rays H. Y. Jiang & Gang Ning & Yaming , 2024. "The DEAD-box RNA helicase PfDOZI imposes opposing actions on RNA metabolism in Plasmodium falciparum," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    2. Stanley C. Xie & Yinuo Wang & Craig J. Morton & Riley D. Metcalfe & Con Dogovski & Charisse Flerida A. Pasaje & Elyse Dunn & Madeline R. Luth & Krittikorn Kumpornsin & Eva S. Istvan & Joon Sung Park &, 2024. "Reaction hijacking inhibition of Plasmodium falciparum asparagine tRNA synthetase," Nature Communications, Nature, vol. 15(1), pages 1-18, December.

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