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Eukaryotic Cell, November 2007, p. 2147-2156, Vol. 6, No. 11
1535-9778/07/$08.00+0     doi:10.1128/EC.00262-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Artemisinin Induces Calcium-Dependent Protein Secretion in the Protozoan Parasite Toxoplasma gondii{triangledown} ,{dagger}

Kisaburo Nagamune, Wandy L. Beatty, and L. David Sibley*

Department of Molecular Microbiology, Washington University School of Medicine, 660 S. Euclid Ave., St. Louis, Missouri 63110

Received 21 July 2007/ Accepted 20 August 2007

Intracellular calcium controls several crucial cellular events in apicomplexan parasites, including protein secretion, motility, and invasion into and egress from host cells. The plant compound thapsigargin inhibits the sarcoplasmic-endoplasmic reticulum calcium ATPase (SERCA), resulting in elevated calcium and induction of protein secretion in Toxoplasma gondii. Artemisinins are natural products that show potent and selective activity against parasites, making them useful for the treatment of malaria. While the mechanism of action is uncertain, previous studies have suggested that artemisinin may inhibit SERCA, thus disrupting calcium homeostasis. We cloned the single-copy gene encoding SERCA in T. gondii (TgSERCA) and demonstrate that the protein localizes to the endoplasmic reticulum in the parasite. In extracellular parasites, TgSERCA partially relocalized to the apical pole, a highly active site for regulated secretion of micronemes. TgSERCA complemented a calcium ATPase-defective yeast mutant, and this activity was inhibited by either thapsigargin or artemisinin. Treatment of T. gondii with artemisinin triggered calcium-dependent secretion of microneme proteins, similar to the SERCA inhibitor thapsigargin. Artemisinin treatment also altered intracellular calcium in parasites by increasing the periodicity of calcium oscillations and inducing recurrent, strong calcium spikes, as imaged using Fluo-4 labeling. Collectively, these results demonstrate that artemisinin perturbs calcium homeostasis in T. gondii, supporting the idea that Ca2+-ATPases are potential drug targets in parasites.

* Corresponding author. Mailing address: Department of Molecular Microbiology, Washington University School of Medicine, 660 S. Euclid Ave., St. Louis, MO 63110. Phone: (314) 362-8873. Fax: (314) 286-0060. E-mail: sibley{at}borcim.wustl.edu

{triangledown} Published ahead of print on 31 August 2007.

{dagger} Supplemental material for this article may be found at http://ec.asm.org/.

Eukaryotic Cell, November 2007, p. 2147-2156, Vol. 6, No. 11
1535-9778/07/$08.00+0     doi:10.1128/EC.00262-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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