Department of Immunology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, China.
Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Institute of Translational Medicine, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, 310029, China.
Adv Sci (Weinh). 2024 Aug;11(32):e2400952. doi: 10.1002/advs.202400952. Epub 2024 Jun 21.
Toxoplasma gondii (T. gondii)-associated polymorphic effector proteins are crucial in parasite development and regulating host anti-T. gondii immune responses. However, the mechanism remains obscure. Here, it is shown that Toxoplasma effector dense granules 4 (GRA4) restricts host IFN-I activation. Infection with Δgra4 mutant T. gondii strain induces stronger IFN-I responses and poses a severe threat to host health. Mechanistically, GRA4 binds to phosphorylated TBK1 to promote TRIM27-catalyzed K48-ubiquitination at Lys251/Lys372 residues, which enhances its recognition by autophagy receptor p62, ultimately leading to TBK1 autophagic degradation. Furthermore, an avirulent Δgra4 strain (ME49Δompdc/gra4) is constructed for tumor immunotherapy due to its ability to enhance IFN-I production. Earlier vaccination with ME49Δompdc/gra4 confers complete host resistance to the tumor compared with the classical ME49Δompdc treatment. Notably, ME49Δompdc/gra4 vaccination induces a specific CD64MAR-1CD11b dendritic cell subset, thereby enhancing T cell anti-tumor responses. Overall, these findings identify the negative role of T. gondii GRA4 in modulating host IFN-I signaling and suggest that GRA4 can be a potential target for the development of T. gondii vaccines and tumor immunotherapy.
刚地弓形虫（Toxoplasma gondii）相关的多态效应蛋白在寄生虫的发育和调控宿主抗弓形虫免疫反应中起着至关重要的作用。然而，其机制尚不清楚。本研究表明，弓形虫效应致密颗粒 4（GRA4）限制了宿主 IFN-I 的激活。感染Δgra4 突变的弓形虫株会诱导更强的 IFN-I 反应，并对宿主健康构成严重威胁。在机制上，GRA4 与磷酸化 TBK1 结合，促进 TRIM27 催化的 Lys251/Lys372 残基上的 K48-泛素化，从而增强其被自噬受体 p62 的识别，最终导致 TBK1 自噬降解。此外，由于其增强 IFN-I 产生的能力，构建了一种无毒的Δgra4 株（ME49Δompdc/gra4）用于肿瘤免疫治疗。与经典的 ME49Δompdc 治疗相比，早期接种 ME49Δompdc/gra4 可使宿主完全抵抗肿瘤。值得注意的是，ME49Δompdc/gra4 疫苗接种可诱导特定的 CD64MAR-1CD11b 树突状细胞亚群，从而增强 T 细胞的抗肿瘤反应。总的来说，这些发现确定了弓形虫 GRA4 在调节宿主 IFN-I 信号中的负向作用，并表明 GRA4 可能成为开发弓形虫疫苗和肿瘤免疫治疗的潜在靶点。
