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

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 is not well-characterized. Here, we found that cyclic GMP-AMP synthase (cGAS), a sensor of foreign dsDNA, is required for activation of anti- immune signaling in a mouse model. We also found that mice deficient in STING ( mice) are much more susceptible to infection than WT mice. Of note, the induction of inflammatory cytokines, type I IFNs, and interferon-stimulated genes in the spleen from mice was significantly impaired. mice exhibited more severe symptoms than cGAS-deficient mice after infection. Interestingly, we found that the dense granule protein GRA15 from 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 failed to elicit robust innate immune responses compared with WT Consequently, GRA15 was more virulent and caused higher mortality of WT mice but not mice upon infection. Together, infection triggers cGAS/STING signaling, which is enhanced by GRA15 in a STING- and TRAF-dependent manner.