The GRA15 protein from Toxoplasma gondii enhances host defense responses by activating the interferon stimulator STING
The GRA15 protein from Toxoplasma gondii enhances host defense responses by activating the interferon stimulator STING
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弓形虫 GRA15 蛋白通过激活干扰素刺激剂 STING 增强宿主防御反应
DOI：
10.1074/jbc.ra119.009172
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发表时间：
2019-08
期刊：
影响因子：
--
通讯作者：
游富平
中科院分区：
文献类型：
--
作者：
游富平
刚地弓形虫是一种重要的嗜神经病原体，它能在人体中建立潜伏感染，可导致免疫功能低下个体患上弓形虫病。它在宿主细胞内进行繁殖，并演化出多种策略来操控宿主的免疫……（原文此处“immu”不完整，推测完整单词可能是“immune”，意为“免疫的” ，“immune system”即“免疫系统” ）
Toxoplasma gondii is an important neurotropic pathogen that establishes latent infections in humans that can cause toxoplasmosis in immunocompromised individuals. It replicates inside host cells and has developed several strategies to manipulate host immune responses. However, the cytoplasmic pathogen-sensing pathway that detects T. gondii is not well-characterized. Here, we found that cyclic GMP-AMP synthase (cGAS), a sensor of foreign dsDNA, is required for activation of anti-T. gondii immune signaling in a mouse model. We also found that mice deficient in STING (Stinggt/gt mice) are much more susceptible to T. gondii infection than WT mice. Of note, the induction of inflammatory cytokines, type I IFNs, and interferon-stimulated genes in the spleen from Stinggt/gt mice was significantly impaired. Stinggt/gt mice exhibited more severe symptoms than cGAS-deficient mice after T. gondii infection. Interestingly, we found that the dense granule protein GRA15 from T. gondii is secreted into the host cell cytoplasm and then localizes to the endoplasmic reticulum, mediated by the second transmembrane motif in GRA15, which is essential for activating STING and innate immune responses. Mechanistically, GRA15 promoted STING polyubiquitination at Lys-337 and STING oligomerization in a TRAF protein-dependent manner. Accordingly, GRA15-deficient T. gondii failed to elicit robust innate immune responses compared with WT T. gondii. Consequently, GRA15−/− T. gondii was more virulent and caused higher mortality of WT mice but not Stinggt/gt mice upon infection. Together, T. gondii infection triggers cGAS/STING signaling, which is enhanced by GRA15 in a STING- and TRAF-dependent manner.
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影响因子：
6.4
作者：
Gov L;Karimzadeh A;Ueno N;Lodoen MB
通讯作者：
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影响因子：
14.9
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Kuleshov MV;Jones MR;Rouillard AD;Fernandez NF;Duan Q;Wang Z;Koplev S;Jenkins SL;Jagodnik KM;Lachmann A;McDermott MG;Monteiro CD;Gundersen GW;Ma'ayan A
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3.1
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影响因子：
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影响因子：
6.7
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