UMR 5163, LAPM, Centre National de la Recherche Scientifique, 38041 Grenoble, France.
Cell Host Microbe. 2013 Apr 17;13(4):489-500. doi: 10.1016/j.chom.2013.03.002.
After invading host cells, Toxoplasma gondii multiplies within a parasitophorous vacuole (PV) that is maintained by parasite proteins secreted from organelles called dense granules. Most dense granule proteins remain within the PV, and few are known to access the host cell cytosol. We identify GRA16 as a dense granule protein that is exported through the PV membrane and reaches the host cell nucleus, where it positively modulates genes involved in cell-cycle progression and the p53 tumor suppressor pathway. GRA16 binds two host enzymes, the deubiquitinase HAUSP and PP2A phosphatase, which exert several functions, including regulation of p53 and the cell cycle. GRA16 alters p53 levels in a HAUSP-dependent manner and induces nuclear translocation of the PP2A holoenzyme. Additionally, certain GRA16-deficient strains exhibit attenuated virulence, indicating the importance of these host alterations in pathogenesis. Therefore, GRA16 represents a potentially emerging subfamily of exported dense granule proteins that modulate host function.
刚地弓形虫在侵入宿主细胞后，会在由致密颗粒（一种细胞器）分泌的寄生虫蛋白所维持的寄生泡（PV）中进行复制。大多数致密颗粒蛋白仍留在 PV 内，只有少数已知能进入宿主细胞质。我们鉴定出 GRA16 是一种致密颗粒蛋白，它通过 PV 膜输出并到达宿主细胞核，在那里它正向调节参与细胞周期进程和 p53 肿瘤抑制途径的基因。GRA16 结合两种宿主酶，去泛素化酶 HAUSP 和 PP2A 磷酸酶，它们发挥多种功能，包括调节 p53 和细胞周期。GRA16 以依赖 HAUSP 的方式改变 p53 水平，并诱导 PP2A 全酶的核转位。此外，某些缺乏 GRA16 的菌株表现出毒力减弱，表明这些宿主改变在发病机制中的重要性。因此，GRA16 代表了一类潜在的新兴的、能调节宿主功能的分泌致密颗粒蛋白亚家族。
