Dynamique des Interactions Membranaires Normales et Pathologiques, UMR5235 CNRS, INSERM, Université de Montpellier, Montpellier, France.
Department of Biology, Boston College, Chestnut Hill, MA, 02467, USA.
Cell Mol Life Sci. 2018 Dec;75(23):4417-4443. doi: 10.1007/s00018-018-2889-6. Epub 2018 Jul 26.
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.
肉足鞭毛门包含疟原虫和隐孢子虫等致命病原体。肉足鞭毛门的细胞分裂在机制上与哺乳动物宿主不同，这可能代表了有吸引力的药物靶点来源。根据物种的不同，顶复门寄生虫可以调节细胞分裂的输出，一次产生 2 到数千个子细胞。它们细胞分裂机制的固有灵活性使这些寄生虫能够适应不同的小生境，促进其传播。刚地弓形虫速殖子使用一种称为内共生性的独特形式的细胞分裂来分裂。这个过程涉及一轮 DNA 复制、封闭的核有丝分裂，以及在母体内组装两个子细胞。在高等真核生物中，四亚基染色体乘客复合物（CPC）（Aurora 激酶 B（ARKB）/INCENP/Borealin/Survivin）通过分离不正确的动粒微管连接物来促进染色体双定向，在控制细胞分裂保真度方面发挥着重要作用。在此，我们报告了刚地弓形虫 CPC（Aurora 激酶 1（Ark1）/INCENP1/INCENP2）的特征。我们表明，CPC 以细胞周期依赖性方式表现出动态定位。TgArk1 与两个 TgINCENPs 相互作用，TgINCENP2 对于其核易位是必需的。虽然 TgINCENP1 似乎是可有可无的，但干扰 TgArk1 或 TgINCENP2 会导致明显的分裂和生长缺陷。大量抗癌药物开发工作集中在靶向人类 ARKB 上。用低剂量的 hesperadin 处理寄生虫，hesperadin 在较高浓度下是人类 ARKB 的已知抑制剂，可模拟 TgArk1 和 TgINCENP2 突变体。总的来说，我们的研究为顶复门细胞周期控制的机制提供了新的见解，并强调了 TgArk1 作为潜在的药物靶点。
