Bhaskaran Maanasa, Mudiyam Venkat, Mouveaux Thomas, Roger Emmanuel, Gissot Mathieu
University of Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019-UMR 9017-CIIL-Center for Infection and Immunity of Lille, Lille, France.
PLoS Pathog. 2024 Dec 30;20(12):e1012810. doi: 10.1371/journal.ppat.1012810. eCollection 2024 Dec.
Pathogenesis of Toxoplasma gondii in the intermediate host is based on the tachyzoite ability to divide rapidly to produce significant amount of daughter cells in a reduce time frame. The regulation of the cell-cycle specific expression program is therefore key to their proliferation. Transcriptional regulation has a crucial role in establishing this expression program and transcription factors regulates many aspects of tachyzoite cell cycle. We explored the role of two ApiAP2 transcription factors, TgAP2XII-9 and TgAP2III-2, during the cell cycle of the tachyzoite form. While TgAP2III-2 has only a minor impact on the tachyzoite proliferation, we show that TgAP2XII-9 regulates many aspects of the cell cycle including the proper assembly of the daughter cells inner membrane complex and temporal expression of many virulence genes. Creation of a double mutant strain for TgAP2XII-9 and TgAP2III-2 shows that TgAP2XII-9 had a prominent role during daughter cell assembly. Using transcriptomics and Cut&Tag, we demonstrate that TgAP2XII-9 mainly acts through the transcriptional control of at least 300 genes promoters. Interestingly, TgAP2XII-9 plays a crucial role repressing the expression of genes necessary for budding initiation and activating genes necessary for microneme de novo formation. We also explored the importance of the AP2 domain of TgAP2XII-9 demonstrating its critical role to exert its function. Therefore, we showed that TgAP2XII-9 is a crucial transcription factor which is key to daughter cell assembly post budding initiation.
刚地弓形虫在中间宿主体内的发病机制基于速殖子能够迅速分裂，在较短时间内产生大量子细胞。因此，细胞周期特异性表达程序的调控是其增殖的关键。转录调控在建立这种表达程序中起着至关重要的作用，转录因子调节速殖子细胞周期的许多方面。我们探讨了两种ApiAP2转录因子TgAP2XII-9和TgAP2III-2在速殖子细胞周期中的作用。虽然TgAP2III-2对速殖子增殖的影响较小，但我们发现TgAP2XII-9调节细胞周期的许多方面，包括子细胞内膜复合体的正确组装和许多毒力基因的时序表达。构建TgAP2XII-9和TgAP2III-2的双突变株表明，TgAP2XII-9在子细胞组装过程中起重要作用。通过转录组学和Cut&Tag技术，我们证明TgAP2XII-9主要通过对至少300个基因启动子的转录控制发挥作用。有趣的是，TgAP2XII-9在抑制出芽起始所需基因的表达和激活微线体从头形成所需基因的表达方面起关键作用。我们还探讨了TgAP2XII-9的AP2结构域的重要性，证明了其发挥功能的关键作用。因此，我们表明TgAP2XII-9是一种关键的转录因子，是出芽起始后子细胞组装的关键。
