Encephalitis is mediated by ROP18 of Toxoplasma gondii, a severe pathogen in AIDS patients
Encephalitis is mediated by ROP18 of Toxoplasma gondii, a severe pathogen in AIDS patients
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脑炎是由弓形虫 ROP18 介导的，弓形虫是艾滋病患者的一种严重病原体
DOI：
10.1073/pnas.1801118115
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发表时间：
2018-06-05
影响因子：
11.1
通讯作者：
Du, Jian
中科院分区：
文献类型：
--
作者：
An, Ran;Tang, Yuewen;Du, Jian
作为一种嗜神经寄生虫，弓形虫在整个CNS感染过程中主要与神经元相互作用，并对大脑造成严重损害。在严重免疫功能障碍的患者中，休眠的包囊缓殖子可以重新激活为快速复制的速殖子，并可能对大脑造成损害。我们报告，内质网（ER）相关蛋白，RTN 1-C，是ROP 18激酶的底物。RTN 1-C的ROP 18磷酸化触发ER应激介导的凋亡。磷酸化的RTN 1-C通过减弱组蛋白去乙酰化酶的活性来增强GRP 78乙酰化，并且与神经细胞凋亡相关。这些结果将弓形虫的效应器ROP 18与CNS主要表达的蛋白RTN 1-C以及通过GRP 78乙酰化的ER应激诱导的细胞凋亡联系起来，这可能为弓形虫优先侵入中枢神经系统提供新的见解。嗜神经性寄生虫弓形虫是一种全球性分布的哺乳动物宿主，包括人类的寄生原虫。在感染过程中，CNS是受侵组织中最常见的受损器官。多态性棒状体蛋白18（ROP 18）是一种关键的丝氨酸（Ser）/苏氨酸（Thr）激酶，其磷酸化宿主蛋白以调节急性毒力。然而，向神经性的基础和ROP 18发挥神经发病机制的特定底物仍然未知。使用质谱法，我们进行了蛋白质组学分析的蛋白质，选择性地结合到活性ROP 18和确定RTN 1-C，内质网（ER）蛋白，优先在中枢神经系统中表达。我们证明了ROP 18与RTN 1-C的N-末端部分相关，并特异性磷酸化RTN 1-C的Ser 7/134和Thr 4/8/118。RTN 1-C的ROP 18磷酸化触发神经细胞中ER应激介导的凋亡值得注意的是，RTN 1-C的ROP 18磷酸化通过减弱组蛋白脱乙酰酶（HDAC）的活性来增强葡萄糖调节蛋白78（GRP 78）乙酰化，并且该事件与神经细胞凋亡的增加相关。这些结果清楚地表明RTN 1-C和HDAC都参与T.弓形虫感染时弓形虫ROP 18介导的脑炎发病机制
Significance As a neurotropic parasite, Toxoplasma predominantly interacts with neurons throughout CNS infection and causes severe damage to the brain. In patients with severe immune dysfunction, dormant encysted bradyzoites can reactivate into fast-replicating tachyzoites and may cause damage to the brain. We report that an endoplasmic reticulum (ER)-associated protein, RTN1-C, is a substrate of ROP18 kinase. ROP18 phosphorylation of RTN1-C triggers ER stress-mediated apoptosis. Phosphorylated RTN1-C enhances GRP78 acetylation via attenuating the activity of histone deacetylases and is associated with neural apoptosis. These results link Toxoplasma’s effector ROP18 to RTN1-C, the CNS predominantly expressed protein, as well as ER stress-induced apoptosis via GRP78 acetylation, which may provide new insight into the preferential invasion of the central nervous system by Toxoplasma. The neurotropic parasite Toxoplasma gondii is a globally distributed parasitic protozoan among mammalian hosts, including humans. During the course of infection, the CNS is the most commonly damaged organ among invaded tissues. The polymorphic rhoptry protein 18 (ROP18) is a key serine (Ser)/threonine (Thr) kinase that phosphorylates host proteins to modulate acute virulence. However, the basis of neurotropism and the specific substrates through which ROP18 exerts neuropathogenesis remain unknown. Using mass spectrometry, we performed proteomic analysis of proteins that selectively bind to active ROP18 and identified RTN1-C, an endoplasmic reticulum (ER) protein that is preferentially expressed in the CNS. We demonstrated that ROP18 is associated with the N-terminal portion of RTN1-C and specifically phosphorylates RTN1-C at Ser7/134 and Thr4/8/118. ROP18 phosphorylation of RTN1-C triggers ER stress-mediated apoptosis in neural cells. Remarkably, ROP18 phosphorylation of RTN1-C enhances glucose-regulated protein 78 (GRP78) acetylation by attenuating the activity of histone deacetylase (HDAC), and this event is associated with an increase of neural apoptosis. These results clearly demonstrate that both RTN1-C and HDACs are involved in T. gondii ROP18-mediated pathogenesis of encephalitis during Toxoplasma infection.