The GRA15 protein from Toxoplasma gondii enhances host defense responses by activating the interferon stimulator STING

作者：Peiyan Wang, Siji Li, Yingchi Zhao, Baohuan Zhang, Yunfei Li, Shengde Liu, Hongqiang Du, Lili Cao, Meiling Ou, Xiaohong Ye, Peng Li, Xiang Gao, Penghua Wang, Chunxia Jing, Feng Shao, Guang Yang, Fuping You · 发表于：Journal of Biological Chemistry · 年份：2019 · DOI：10.1074/jbc.ra119.009172 · 被引用次数：51 · 研究领域：Toxoplasma gondii Research Studies、interferon and immune responses、Herpesvirus Infections and Treatments

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 (Sting gt/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 Sting gt/gt mice was significantly impaired. Sting gt/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. Conse-quently, GRA15 / T. gondii was more virulent and ...