Toxoplasma gondii chromosomal passenger complex is essential for the organization of a functional mitotic spindle: a prerequisite for productive endodyogeny
The phylum Apicomplexa encompasses deadly pathogens such as malaria and Cryptosporidium. Apicomplexa cell division is mechanistically divergent from that of their mammalian host, potentially representing an attractive source of drug targets. Depending on the species, apicomplexan parasites can modulate the output of cell division, producing two to thousands of daughter cells at once. The inherent flexibility of their cell division mechanisms allows these parasites to adapt to different niches, facilitating their dissemination. Toxoplasma gondii tachyzoites divide using a unique form of cell division called endodyogeny. This process involves a single round of DNA replication, closed nuclear mitosis, and assembly of two daughter cells within a mother. In higher Eukaryotes, the four-subunit chromosomal passenger complex (CPC) (Aurora kinase B (ARKB)/INCENP/Borealin/Survivin) promotes chromosome bi-orientation by detaching incorrect kinetochore–microtubule attachments, playing an essential role in controlling cell division fidelity. Herein, we report the characterization of the Toxoplasma CPC (Aurora kinase 1 (Ark1)/INCENP1/INCENP2). We show that the CPC exhibits dynamic localization in a cell cycle-dependent manner. TgArk1 interacts with both TgINCENPs, with TgINCENP2 being essential for its translocation to the nucleus. While TgINCENP1 appears to be dispensable, interfering with TgArk1 or TgINCENP2 results in pronounced division and growth defects. Significant anti-cancer drug development efforts have focused on targeting human ARKB. Parasite treatment with low doses of hesperadin, a known inhibitor of human ARKB at higher concentrations, phenocopies the TgArk1 and TgINCENP2 mutants. Overall, our study provides new insights into the mechanisms underpinning cell cycle control in Apicomplexa, and highlights TgArk1 as potential drug target.
KeywordsApicomplexa Toxoplasma gondii Cytokinesis Mitosis Centrosome Kinetochore Centromere Spindle Chromosomal passenger complex Aurora kinase Endodyogeny Inner membrane complex
Aurora-related kinase 1
Inner centromere protein
Trans-activator Trap identified
Inner membrane complex
Nuclear filamentous 2
Microtubule-associated protein RP/EB family member
We wish to thank Dominique Soldati-Favre, Vern Carruthers, Lilach Sheiner, Sebastian Lourido, Boris Striepen, Markus Meissner, Peter Bradley, Mathieu Gissot, Christian Doerig, Con Beckers, Iain Cheeseman, Jose Garcia-Bustos, Henri Vial and Marjorie Bienvenu for their kind gift of cell lines, hesperadin drug, plasmids or antibodies, for advices and technical assistance. We also thank the “Montpellier Ressources imagerie” platform, and the electron microscopy facility of the University of Montpellier (MEA), for their assistance in light and electron microscopy experiments, respectively. Dr. Wassim DAHER, Dr. Juliette Morlon-Guyot and Dr. Maryse LEBRUN are INSERM researchers. This work was made possible through core support from the Fondation pour la Recherche Médicale (Equipe FRMDEQ20170336725), the Labex Parafrap (ANR-11-LABX-0024), and National Institute of Health Grants AI110690, AI110638, and AI128136.
Compliance with ethical standards
Conflict of interest
The authors declare that there are no conflicts of interest.
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