Effects of different drugs and hormone treatment on Toxoplasma gondii glutathione S-transferase 2.
Effects of different drugs and hormone treatment on Toxoplasma gondii glutathione S-transferase 2.
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不同药物和激素治疗对弓形虫谷胱甘肽S-转移酶2的影响
DOI：
10.1186/s13071-022-05589-w
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发表时间：
2022-12-12
影响因子：
3.2
通讯作者：
Liu, Qun
中科院分区：
文献类型：
--
作者：
Li, Shuang;Ying, Zhu;Xue, Yangfei;Sun, Zhepeng;Liu, Jing;Liu, Qun
谷胱甘肽S-转移酶（GST）在真核生物中具有多种功能，如解毒内源性/外源性有害物质以保护细胞免受氧化损伤、参与甾醇合成和代谢、调节信号通路等。我们之前的工作发现了弓形虫中一种重要的GST蛋白，称为TgGST 2，它有助于囊泡运输，该蛋白的缺失显着降低了寄生虫的毒力。同时，我们认为TgGST 2可能还参与了寄生虫生命活动的其他途径。用trRosetta和Autodock维纳软件预测TgGST 2、雌二醇（E2）和孕酮（P4）的三级结构，用PyMol的GetBox Plugin分析结合位点，用Discovery Studio plots软件评价结合能力。通过谷胱甘肽S-转移酶活性测定和间接免疫荧光法（IFA）检测E2和P4对TgGST 2的影响，并通过TgGST 2的定位观察来评价其对不同药物的反应能力。TgGST 2可与外源性E2和P4结合，且酶活性受激素浓度依赖性抑制。经P4处理后，TgGST 2的定位由高尔基体和囊泡变为空心环，导致分子转运蛋白Sortilin（VPS 10）和微线体蛋白（M2 AP和MIC 2）的定位异常，最终影响寄生虫的生命活动，而E2对其影响不明显。抗真菌药（伏立康唑和克拉霉素）、抗癌药（KU-60019、WYE-132和SH 5 -07）和抗球虫药（地硝托胺和地克珠利）对TgGST 2的作用不同，使TgGST 2的定位呈现点状、圆形和杆状等不同的形态。我们的研究表明，TgGST 2在甾醇治疗中起作用，并可受P4影响，导致寄生虫运动缺陷。TgGST 2发挥不同的作用，以响应药物本身的不同性质。它对不同药物的反应性意味着开发针对弓形虫和相关致病性寄生虫的药物的可行靶点。在线版本包含补充材料，可通过10.1186/s13071-022-05589-w获得。
Glutathione S-transferase (GST) in eukaryotic organisms has multiple functions such as detoxifying endogenous/exogenous harmful substances to protect cells from oxidative damage, participating in sterol synthesis and metabolism, and regulating signaling pathways. Our previous work identified an important GST protein in Toxoplasma that contributes to vesicle trafficking called TgGST2, the deletion of which significantly reduces the virulence of the parasite. Meanwhile, we considered that TgGST2 may also play a role in other pathways of parasite life activities. The tertiary structures of TgGST2 as well as estradiol (E2) and progesterone (P4) were predicted by trRosetta and Autodock Vina software, the binding sites were analyzed by PyMol's GetBox Plugin, and the binding capacity was evaluated using Discovery Studio plots software. We examined the influence of E2 and P4 on TgGST2 via glutathione S-transferase enzyme activity and indirect immunofluorescence assay (IFA) and through the localization observation of TgGST2 to evaluate its response ability in different drugs. TgGST2 could bind to exogenous E2 and P4, and that enzymatic activity was inhibited by the hormones in a concentration-dependent manner. Upon P4 treatment, the localization of TgGST2 changed from Golgi and vesicles to hollow circles, leading to abnormal localization of the molecular transporter Sortilin (VPS10) and microneme proteins (M2AP and MIC2), which ultimately affect the parasite life activities, but E2 had no significant effect. Moreover, diverse types of drugs had divergent effects on TgGST2, among which treatment with antifungal agents (voriconazole and clarithromycin), anticarcinogens (KU-60019, WYE-132 and SH5-07) and coccidiostats (dinitolmide and diclazuril) made the localization of TgGST2 appear in different forms, including dots, circles and rod shaped. Our study shows that TgGST2 plays a role in sterol treatment and can be affected by P4, which leads to deficient parasite motility. TgGST2 exerts divergent effects in response to the different properties of the drugs themselves. Its responsiveness to diverse drugs implies a viable target for the development of drugs directed against Toxoplasma and related pathogenic parasites. The online version contains supplementary material available at 10.1186/s13071-022-05589-w.
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