Artemisinin kills malaria parasites by damaging proteins and inhibiting the proteasome View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2018-12

AUTHORS

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. Spillman, Leann Tilley

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. More... »

PAGES

3801

References to SciGraph publications

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  • Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1038/s41467-018-06221-1

    DOI

    http://dx.doi.org/10.1038/s41467-018-06221-1

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1106952172

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/30228310


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